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Since the introduction of ciclosporin for psoriasis buy telmisartan 20 mg lowest price pulse pressure vs heart rate, much Topical adrenal corticosteroids act principally by reduc- research has focused on new ways of disrupting T lympho- ing inflammation telmisartan 20mg discount blood pressure drugs. Application order telmisartan 80 mg free shipping arrhythmia nos, especially under occlusive cytes and the cytokines involved in the induction and dressings, can be very effective at suppressing the disease, maintenance of psoriasis. These drugs target specific cellu- but increased doses (concentrations) become necessary lar events, e. The exact role of these For this reason potent corticosteroids should never be used promising therapies is still evolving. Methotrexate is particularly liable to recur in a more unstable form when treatment of use if there is associated disabling arthritis. Platelet is withdrawn, as it must be if complications of long-term count, renal and liver function must be monitored regu- steroid therapy are to be avoided. They The last decade has witnessed a significant advance in the inhibit cell proliferation and encourage cell differentiation. Acitretin should be used in these to be introduced, the T-cell inhibitor efalizumab, courses (6–9 months) with intervals (3–4 months). It is ter- was withdrawn because ofa rareassociation withprogressive atogenic, like the other vitamin A derivatives. He admitted to lighting a cigarette drug approval and pharmacovigilance processes for fully just before the fire, the path of which corresponded to the distribution measuring the safety of a drug. Patients and clinicians need of the tar on his body (Fader D J, Metzman M S 1994 Smoking, tar, and psoriasis: a dangerous combination. New England Journal of to be aware of the relative completeness and limitations of Medicine 330:1541). Women of asis requires considerable judgement and choice will de- childbearing potential should be fully informed of pend on the patient’s sex, age and the severity of the this risk, pregnancy-tested before commencement condition. Topical therapies such as calcipotriol, tar or and use contraception for 4 weeks before, during dithranol-containing compounds should be the mainstay and for 4 weeks after cessation. Topical corticosteroids can be effects are described, including mood change and used for psoriasis inversus under close supervision, as over- severe depression. The objective is to reduce androgen for widespread psoriasis where compliance with topical production or effect by using (1) oestrogen, to suppress treatments is difficult. Resistant disease is best managed hypothalamic–pituitary gonadotrophin production, or by the specialist who may utilise a rotation of treatments, (2) an antiandrogen (cyproterone). Fumaric acid compounds, hy- containing 50 micrograms of oestrogen diminishes droxyurea and specific biological agents are useful for sebum secretion by 40%. Acne vulgaris results from disordered function of the pilo- sebaceous follicle whereby abnormal keratin and sebum Urticaria (the production of which is androgen driven) form debris that plugs the mouth of the follicle. Propionibacterium acnes Acute urticaria (named after its similarity to the sting of colonises the debris. Bacterial action releases inflammatory a nettle, Urtica) and angioedema usually respond well fatty acids from the sebum, resulting in inflammation. A sys- The following measures are used progressively and sel- temic corticosteroid may be needed in severe cases, e. Terfenadine is also effective, but may cause dan- resistance is not a problem; benefit is due to gerous cardiac arrhythmias if the recommended dose is suppression of bacterial lipolysis of sebum, which exceeded or if it is administered with drugs (or grapefruit generates inflammatory fatty acids. But lack of sleep in- because of adverse effects, including raised intracranial creases the intensity of itch (similar to pain), and a sedating pressure and drug-induced lupus. H2-receptor antihis- • Vitamin A (retinoic acid) derivatives reduce sebum tamines may be added for particularly resistant cases. Tretinoin should be avoided in sunny weather and 11Therisk ofbirthdefectinachild ofawoman whohas takenisotretinoin in pregnancy. There can be no doubt that there orally is highly effective (a single course of treatment has been irresponsible prescribing of this drug, e. The fact that a drug with such a grave effect is still permitted to be available is attributed to its high efficacy. In Europe, women of of patients), but is known to be a serious teratogen; childbearing age must comply with a pregnancy prevention its use should generally be confined to the more programme and be monitored monthly while on a course of severe cystic and conglobate cases, where other isotretinoin. Long-term oral methotrexate or intravenous immunoglobulin) may be immunosuppression with ciclosporin, mycophenylate or required. Delay in initiating the treatment may lead to death from laryngeal oedema (try adrenaline/epinephrine i. Hereditary angioedema does not manifest as simple Topical sodium fusidate and mupirocin are preferred (as urticaria. Absorption of neomycin from all top- ical preparations can cause serious injury to the eighth Atopic dermatitis is a chronic condition, and treatment must cranial nerve. When prolonged treatment is required, topical antisep- Successful management includes the elimination of precip- tics (e. Combination of an antimicrobial drug with a corticoste- Immunological triggers of atopic dermatitis vary and roid (to suppress inflammation) can be useful for second- can include aeroallergens, detergents (including soaps), arily infected eczema. Identification and The disadvantages of antimicrobials are contact allergy modification of these factors is useful. Infected leg ulcers generally do not benefit from long-term In subacute and chronic disease, skin care with occlusive antimicrobials, although topical metronidazole is useful emollients helps to offset the xerosis (dryness) that creates when the ulcer is malodorous due to colonisation with microfissures in the skin and disturbs its normal barrier Gram-negative organisms. Topical corticosteroids form the cornerstone of dressing with compression) is preferred if antimicrobial pharmacological therapy. Cellulitis requires systemic chemotherapy initially consecutive weeks to minimise the likelihood of unwanted with benzylpenicillin and flucloxacillin. Infected burns are treated with a variety of antimicrobials, The calcineurin inhibitors, tacrolimus and pimecroli- including silver sulfadiazine and mupirocin. Superficial dermatophyte or Candida but they do not cause skin atrophy and so are especially infections purely involving the skin can be treated with a useful on the face. It responds to topical antifungals or selenium Sedating H1-receptor antihistamines with anxiolytic sulfide preparations; severe infection may require systemic properties may assist with sleep and nocturnal itch. It tends to recur and regular treatments are week course of systemic corticosteroid is useful, especially frequently necessary. Invasion of hair or nails by a 274 Drugs and the skin Chapter | 17 | dermatophyte or a deep mycosis requires systemic therapy; Disinfection and cleansing of the skin. Terbinafine and gris- stances are used according to circumstances: eofulvin are ineffective against yeasts, for which itracona- For skin preparation prior to injection: ethanol or • zole is an alternative. This implies that the de- n Classification of opioid analgesics gree of pain experienced by the patient may be unrelated to n Pharmacodynamics of opioids the extent of underlying tissue damage, and that emotional n Adverse effects and their management. However, clinicians n Antagonist drugs should recognise that the experience of pain is influenced n Tolerance, dependence and addiction. While drug therapy is an expedient (and familiar) form n Multipurpose adjuvant analgesics n Drugs used in neuropathic pain n Adjuvants used for bone pain. In: Benedetti C, Chapman C R, Giron G n Pharmacotherapy of acute migraine (eds) 1990 Opioid Analgesia: Recent Advances in Systemic Administration. Their cell bodies lie in the dor- Nociception sal root ganglia of the spinal cord or in the trigeminal gang- lia. Different nociceptors encode discrete intensities and Pain modalities of pain, depending upon their expression of Suffering ion-channel receptors. Some of these transducers have been identified, including those that respond to heat (>46 C), cold (<10 C) and direct chem- ical irritants such as capsaicin.
Cyproterone acetate telmisartan 80mg with mastercard blood pressure chart new, a very potent progestin and antiandrogen cheap telmisartan 40mg arrhythmia natural treatment, also produces oligospermia; however purchase telmisartan toronto prehypertension caffeine, it does not cause reliable contraception. This compound destroys elements of the seminiferous epithelium but does not significantly alter the endocrine function of the testis. In Chinese studies, large numbers of men were treated with 20 mg/d of gossypol or gossypol acetic acid for 2 months, followed by a maintenance dosage of 60 mg/wk. Preliminary data indicate that recovery (return of normal sperm count) following discontinuance of gossypol administration is more apt to occur in men whose counts do not fall to extremely low levels and when administration is not continued for more than 2 years. Because of low efficacy and significant toxicity, gossypol has been abandoned as a candidate male contraceptive. Bechlioulis A et al: Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes. Böttner M, Thelen P, Jarry H: Estrogen receptor beta: Tissue distribution and the still largely enigmatic physiological function. Kalantaridou S et al: Premature ovarian failure, endothelial dysfunction, and estrogen-progesterone replacement. Paulmurugan R et al: In vitro and in vivo molecular imaging of estrogen receptor α and β homo- and heterodimerization: exploration of new modes of receptor regulation. She should also be advised to get adequate exercise and increase her calcium and vitamin D intake as treatment for her osteoporosis. Her family history is significant for obesity, diabetes, high blood pressure, and coronary artery disease in both parents and several siblings. Laboratory tests reveal a random blood sugar of 261 mg/dL; this is confirmed with a fasting plasma glucose of 192 mg/dL. A fasting lipid panel reveals total cholesterol 264 mg/dL, triglycerides 255 mg/dL, high-density lipoproteins 43 mg/dL, and low-density lipoproteins 170 mg/dL. Diabetes mellitus is defined as an elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action. The disease states underlying the diagnosis of diabetes mellitus are now classified into four categories: type 1, type 2, other, and gestational diabetes mellitus. Type 1 Diabetes Mellitus The hallmark of type 1 diabetes is selective beta cell (B cell) destruction and severe or absolute insulin deficiency. Although most patients are younger than 30 years of age at the time of diagnosis, the onset can occur at any age. Type 1 diabetes is found in all ethnic groups, but the highest incidence is in people from northern Europe and from Sardinia. Susceptibility appears to involve a multifactorial genetic linkage, but only 10–15% of patients have a positive family history. These antibodies facilitate the diagnosis of type 1a diabetes and can also be used to screen family members at risk for developing the disease. Pharmacologic insulin is administered by injection into the subcutaneous tissue using a manual injection device or an insulin pump that continuously infuses insulin under the skin. Interruption of the insulin replacement therapy can be life-threatening and can result in diabetic ketoacidosis or death. Diabetic ketoacidosis is caused by insufficient or absent insulin and results from excess release of fatty acids and subsequent formation of toxic levels of ketoacids. Some patients with type 1 diabetes have a more indolent autoimmune process and initially retain enough beta cell function to avoid ketosis. They can be treated at first with oral hypoglycemic agents but then need insulin as their beta cell function declines. Type 2 Diabetes Mellitus Type 2 diabetes is characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. A given individual may have more resistance or more beta-cell deficiency, and the abnormalities may be mild or severe. Although insulin is produced by the beta cells in these patients, it is inadequate to overcome the resistance, and the blood glucose rises. Individuals with type 2 diabetes may not require insulin to survive, but 30% or more will benefit from insulin therapy to control blood glucose. Although persons with type 2 diabetes ordinarily do not develop ketosis, ketoacidosis may occur as the result of stress such as infection or the use of medication that enhances resistance, eg, corticosteroids. Dehydration in individuals with untreated or poorly controlled type 2 diabetes can lead to a life-threatening condition called nonketotic hyperosmolar coma. In this condition, the blood glucose may rise to 6–20 times the normal range and an altered mental state develops or the person loses consciousness. Other Specific Types of Diabetes Mellitus The “other” designation refers to multiple other specific causes of an elevated blood glucose: pancreatectomy, pancreatitis, nonpan-creatic diseases, drug therapy, etc. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester. It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges; there are species differences in the amino acids of both chains. Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids (Figure 41–1). Differences in the A and B chains and amino acid modifications for the rapid- acting insulin analogs (aspart, lispro, and glulisine) and long-acting insulin analogs (glargine and detemir) are discussed in the text. Although proinsulin may have some mild hypoglycemic action, C-peptide has no known physiologic function. Granules within the beta cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units. With improved purification techniques, the unit is presently defined on the basis of weight, and present insulin standards used for assay purposes contain 28 units per milligram. Insulin Secretion Insulin is released from pancreatic beta cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Inhibitory signals are hormones including insulin itself, somatostatin, and leptin; α-adrenergic sympathetic activity; chronically elevated glucose; and low concentrations of fatty acids. Decreased outward potassium efflux results in depolarization of the beta cell and opening of voltage-gated calcium channels. The insulin secretagogue drug group (sulfonylureas, meglitinides, and D-phenylalanine) exploits parts of this mechanism. As in muscle and nerve, voltage-gated calcium channels open in response to depolarization, allowing more calcium to enter the cell. Insulin Degradation The liver and kidney are the two main organs that remove insulin from the circulation. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas by virtue of its location as the terminal site of portal vein blood flow, with the kidney removing 35–40% of the endogenous hormone. However, in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30–40%.
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The result of laser epilation is transient and may paradoxically induce excess hair growth in certain individuals Hyperhidrosis Astringents reduce sweat production order telmisartan 80 mg with mastercard blood pressure ranges, especially The characteristic smell is produced by bacterial aluminium chloride hexahydrate buy genuine telmisartan blood pressure medication kills. Sympathectomy is used occasionally but may be complicated by compensatory hyperhidrosis Impetigo Topical antibiotics cheap 20 mg telmisartan overnight delivery arrhythmia urination, e. Other agents include acetretin and auranofin Malignancies Actinic keratoses and Bowen’s disease can be treated with topical 5-fluorouracil (skin irritation is to be expected) or cryotherapy. Extensive lesions may respond to photodynamic therapy: the skin is sensitised using a topical haematoporphyrin derivative, e. Cure: zinc cream or calamine lotion plus above measures Onychomycosis Confirm dermatophyte infection with microscopy and The newer oral antifungals have not been culture. Surgical removal of 6–9 months of once-weekly fluconazole is used for infected nail maybe required and reinfection is fingernail onychomycosis. For toenail disease, common terbinafine is used for 12–16 weeks; 3–4 pulses of itraconazole or fluconazole once per week for 9–15 months can be used 270 Drugs and the skin Chapter | 17 | Table 17. Physical rapid metabolism in humans than in insects, and on measures including regular combing and low absorption) keeping hair short are important Pemphigus and Milder cases can be treated with topical corticosteroids pemphigoid and tetracyclines. Some patients respond to dapsone, minocycline or clofazamine Rosacea Topical metronidazole and systemic tetracycline. Control pustulation in order to prevent Retinoids are useful for severe cases secondary scarring and rhinophyma Scabies (Sarcoptes Permethrin dermal cream. Alternatives include benzyl Apply to all members of the household, scabiei) benzoate or ivermectin (single dose), especially for immediate family or partner. Topical corticosteroid to settle persistent hypersensitivity Seborrhoeic A proprietary shampoo with pyrithione, selenium dermatitis: sulfide or coal tar; ketoconazole shampoo in more dandruff (Pityriasis severe cases. Occasionally a corticosteroid lotion may capitis) be necessary Tinea capitis In children griseofulvin for 6–8 weeks is effective and Antifungal shampoos can reduce active safe. Microsporum will respond to antifungals 6 weeks’ therapy with terbinafine Tinea pedis Most cases will respond to tolnaftate or undecenoic acid creams. Allylamine (terbinafine) creams are possibly more effective than azoles in resistant cases Venous leg ulcers Limb compression is the mainstay of therapy. Otheragentsincludingpentoxifyllineandskingraftsare useful adjuncts to compression therapy Viral warts All treatments are destructive and should be Warts often disappear spontaneously. For plantar warts, formaldehyde or glutaraldehyde; for plantar or anogenital warts, podophyllin (antimitotic). Drugs the effects of topical agents such as calcipotriol (act are used to: by reducing cell division), antimitotic agents like tar • dissolve keratin (keratolysis) (Goeckerman’s regimen) and dithranol (Ingram’s regi- • inhibit cell division. The proliferated cells may be eliminated by a therapy is associated with an increased risk of cutaneous dithranol (antimitotic) preparation applied accurately to squamous cell carcinoma and melanoma development the lesions (but not on the face or scalp) for 1 h and then (especially in those given maintenance treatment). It has a rapid onset of action and is useful in appeared and may produce prolonged remissions of psori- achieving remissions in all forms of psoriasis. Tar (antimitotic) preparations are used in a similar of blood pressure and renal function is mandatory. Severe way, are less irritating to normal skin and are commonly adverse effects, including renal toxicity, preclude its being used for psoriasis of the scalp. Pain behaviour Action potentials that result from the transduction of noxious stimuli are conducted along the axon of the sen- sory neurone into the spinal cord. Conduction of the action potentials in sensory neurones depends on voltage-gated Withdrawal Learning sodium channels, including two that are predominately from social Physical deconditioning helplessness/ expressed in nociceptors; Nav1. Its release can be Quality of life inhibited by ligands that act to activate receptors found on the central terminal of the nociceptors (pre-synaptic inhibition). This results in hyper- of treatment, successful management of pain requires a polarisation of the neurone, which inhibits its activity. For example, substance P is released during high-intensity and repetitive noxious stim- Nociception ulation. The end-result is a progressive increase in the ical process by which pain is perceived is known as nocicep- output from dorsal horn neurones. While the neurobiology of nociception is complex, its is thought to be responsible for the escalation of pain appreciation provides a useful framework for understand- when the skin is repeatedly stimulated by noxious heat – a ing the way analgesics work (Fig. Our nervous system is alerted to actual or potential tissue Nociceptive output from the spinal cord is further mod- injury by the activation of the peripheral terminals ulated by descending inhibitory neurones that originate of highly specialised primary sensory neurones called noci- from supraspinal sites such as the periaqueductal gray or the rostral ventromedial medulla and terminate on 2‘Another event at Elsterhorst had a marked effect on me. The Germans nociceptive neurones in the spinal cord as well as on spinal dumpedayoungSovietprisonerinmywardlateonenight. I had no morphia, just Transmission through these inhibitory pathways is aspirin, which had no effect. I knew very little Russian facilitated by monoamine neurotransmitters such as then and there was no one in the ward who did. I finally instinctively sat down on the bed and took him in my arms, and the screaming noradrenaline/norepinephrine and serotonin. These agents either activate nociceptors directly or sensitise them to subsequent stimuli by parallel activation of intracellular kinases by G- protein-coupled receptors and tyrosine kinase receptors. Activation of descending noradrenergic/norepinergic and/or serotonergic systems, which originate in the brain and brainstem, leads to the activation of spinal inhibitory interneurones (I) thereby resulting in antinociception (http://encref. Poorly controlled post-surgical pain is associated with the development of Classification of clinical pain complications such as pneumonia, myocardial ischaemia, Rational pharmacological treatment of clinical pain de- paralytic ileus and thromboembolism, as well as an in- pends on a number of factors, including the underlying creased risk of the patient developing chronic pain. Effec- cause and duration of pain, the patient’s general medical tive analgesia in this setting not only reduces patient condition and prognosis. Clinical pain is generally di- anxiety and provides subjective comfort, but also helps vided into three broad categories; acute, chronic, and to blunt autonomic and somatic reflex responses. Moreover, research suggests that analgesia given be- level of function should be assessed in detail, focusing fore surgical incision may reduce subsequent postoperative on family relationships (including sexual), social network, pain. It is also important to determine what the pain means to Chronic pain is commonly defined as pain that persists the patient. In some patients, reporting pain may be more beyond the period expected for healing, or pain that is as- socially acceptable than reporting feelings of depression or sociated with progressive, non-malignant disease. In pain may be due to the persistent stimulation of nocicep- cancer patients, in particular, suffering may be due as much tors in areas of ongoing tissue damage (e. In many instances, chronic The patient’s expression of pain represents more than the pain can persist long after the healing of damaged tissue. In some patients, chronic pain presents without any iden- Thorough physical examination is essential, and can tified ongoing tissue damage or antecedent injury. Cancer-related pain refers to pain that is the result of pri- • Dyaesthesia – a painful paraesthesia, e. Analgesics patient’s pain will depend on the type and cause of pain, are classified as opioids and non-opioids (e. Co- as well as the psychological and physical condition of the analgesics or adjuvants are drugs that havea primary indica- patient. A comprehensive evaluation of the pain is, there- tion other than pain but are analgesic in some conditions.
Tablets taken with tween drugs and individuals generic telmisartan 80mg with amex arteria pudenda externa, the phenomenon of first-pass too small a quantity of liquid and in the supine position discount telmisartan uk blood pressure medication photosensitivity, elimination adds to variation in systemic plasma concen- 9 can lodge in the oesophagus with delayed absorption trations telmisartan 20mg visa blood pressure for women, and thus particularly in initial response to the and may even cause ulceration (sustained-release potas- drugs that are subject to this process. In drug overdose, de- sium chloride and doxycycline tablets), especially in the el- creased presystemic elimination with increased bioavail- derly and those with an enlarged left atrium which ability may account for the rapid onset of toxicity with 10 impinges on the oesophagus. Advantages are that the drug is include:8 placed at the site of action (neomycin, anthelminthics), and with non-absorbed drugs the local concentration can be higher than would be safe in the blood. Disadvantages are that drug distribution may be uneven, Analgesics Adrenoceptor Others and in some diseases of the gut the whole thickness of the blockers wall is affected (severe bacillary dysentery, typhoid) and morphine labetalol chlorpromazine propranolol isosorbide dinitrate 9A woman’s failure to respond to antihypertensive medication was explained when she was observed to choke on drinking. Investigation metoprolol nortriptyline revealed a large pharyngeal pouch that was full of tablets and capsules. New England Journal of to sit and take three or four mouthfuls of water (a mouthful ¼ 30 mL) Medicine 352:2211–2221. Sublingual or buccal for systemic effect Disadvantages are the hazard if drug administration is too rapid, as plasma concentration may rise at a rate such that Advantages are that the effect is quick, e. Spitting (brain) circulation time, which is 13 Æ 3 s; with most drugs out the tablet will terminate the effect. Local quent, irritation of the mucous membrane and excessive venous thrombosis is liable to occur with prolonged salivation, which promotes swallowing, so losing the ad- infusion and with bolus doses of irritant formulations, vantages of bypassing presystemic elimination. Infection of the intra- venous catheter and the small thrombi on its tip is also a For systemic effect (suppositories or solutions). Drugs chiefly enter Intramuscular injection the portal system, but those that are subject to hepatic first- Blood flow is greater in the muscles of the upper arm than pass elimination may escape this if they are absorbed from in the gluteal mass and thigh, and increases with physical the lower rectum, which drains directly to the systemic exercise. The degree of presystemic elimination thus Advantages are that the route is reliable, suitable for some depends on distribution within the rectum and this is irritant drugs, and depot preparations (neuroleptics, hor- somewhat unpredictable. Absorption is more rapid than irritates the stomach (aminophylline, indometacin); the following subcutaneous injection (soluble preparations are route is suitable in vomiting, motion sickness, migraine absorbed within 10–30 min). Repeated injections at one site can cause lipo- atrophy, resulting in erratic absorption (see Insulin, Ch. Aerosols are particles dispersed in a gas, the particles Intravenous (bolus or infusion) being small enough to remain in suspension for a long time An intravenous bolus, i. Particle size and Advantages are that the intravenous route gives swift, ef- air-flow velocity are important. Most particles greater than fective and highly predictable blood concentration and al- 5 micrometres in diameter impact in the upper respiratory lows rapid modification of dose, i. Air-flow velocity diminishes 88 General pharmacology Chapter | 8 | considerably as the bronchi progressively divide, promot- ing drug deposition peripherally. Most drugs provide high local concentration for action on bronchi, distribute widely, in part dissolved in body water, in part minimising systemic effects. Distribution Disadvantages are that special apparatus is needed (some is often uneven, for drugs may bind selectively to plasma patients find pressurised aerosols difficult to use to best or tissue proteins or be localised within particular organs. Advantage is the provision of high local concentration Distribution volume without systemic effect (usually11). The pattern of distribution from plasma to other body Disadvantage is that absorption can occur, especially fluids and tissues is a characteristic of each drug that enters when there is tissue destruction so that systemic effects the circulation, and it varies between drugs. Transdermal delivery systems release • If a drug is present mainly in other tissues, the drug through a rate-controlling membrane into the skin distribution volume will be large. In drug overdose, if a ations in plasma concentration associated with other major proportion of the total body load is known to be routes of administration, as is first-pass elimination in in the plasma, i. Glyceryl trinitrate and postmenopausal hormone haemodialysis/filtration is likely to be a useful option (as replacement therapy are available in the form of a sticking is the case with severe salicylate poisoning), but it is an in- plaster attached to the skin or as an ointment (glyceryl appropriate treatment for overdose with dosulepin (see trinitrate). The principle for measuring the distribution volume is essentially that of using a dye to find the volume of a con- 11 tainer filled with liquid. A 70-year-old man reported left breast enlargement and underwent mastectomy; histological examination revealed benign by the concentration of dye once mixing is complete gives gynaecomastia. Tests of the distribution volume of the dye, which is the volume of endocrine function were normal but the patient himself was struck by the container. Similarly, the distribution volume of a drug the fact that his wife had been using a vaginal cream (containing 0. The result of this calculation, the distribution volume, in Selective distribution within the body occurs because of fact only rarely corresponds with a physiological body special affinity between particular drugs and particular space such as extracellular water or total body water, for body constituents. Many drugs bind to proteins in the it is a measure of the volume a drug would apparently oc- plasma; phenothiazines and chloroquine bind to mela- cupy knowing the dose given and the plasma concentration nin-containing tissues, including the retina, which may achieved, and assuming the entire volume is at that concen- explain the occurrence of retinopathy. For this reason, the term apparent distribution vol- concentrate selectively in a particular tissue because of ume is often preferred. Plasma protein and tissue binding The distribution volume of a drug is the volume in Many natural substances circulate around the body partly which it appears to distribute (or which it would free in plasma water and partly bound to plasma proteins; require) if the concentration throughout the body were these include cortisol, thyroxine, iron, copper and, in he- equal to that in plasma, i. Drugs, too, circulate in the protein-bound and free states, and the significance is that the free fraction is pharmacolog- ically active whereas the protein-bound component is a The list in Table 8. The names of those substances that distribute Free and bound fractions are in equilibrium, and free drug removed from the plasma by metabolism, renal function or 14Clearly a problem arises in that the plasma concentration is not dialysis is replaced by drug released from the bound constant but falls after the bolus has been injected. The log concentration–timeline extended back to zero time gives the theoretical plasma concentration at the time the drug substances and drugs. In effect, the assumption is made that drug distributes ative charge at blood pH and a high capacity but low (weak) instantaneously and uniformly through a single compartment, the affinity for many basic drugs, i. This mechanism, although rather theoretical, does usefully characterise drugs according to the extent to which they ily released. Saturation of binding sites on The free, unbound, and therefore pharmacologically ac- plasma proteins in general is unlikely in the doses in which tive percentages of some drugs appear in Table 8. Drugs that are otics) and subjects them to various mechanisms for elimi- normally extensively protein bound should be used with nating chemical intruders. Furosemide 2 (6% in nephrotic Drug-metabolising enzymes developed during evolu- syndrome) tion to enable the body to dispose of lipid-soluble sub- Tolbutamide 2 stances such as hydrocarbons, steroids and alkaloids that are ingested with food. Triamterene 19 (40% in renal disease) Trimethoprim 30 Altering biological activity Theophylline 35 (71% in liver disease) The end-result of metabolism usually is the abolition of biological activity, but various steps in between may have Morphine 65 the following consequences: Digoxin 75 (82% in renal disease) 1. Conversion of one pharmacologically active to Ethosuximide 100 another active substance – this has the effect of prolonging drug action, as shown below. The new metabolite often has reduced biological activity and differ- codeine morphine ent pharmacokinetic properties, e. The most important of these is a large ‘superfamily’ of haem pro- teins, the cytochrome P450 enzymes, which metabolise che- micals from the environment, the diet and drugs. Conversion of a pharmacologically inactive to an active complex process, the drug molecule incorporates one substance (then called a prodrug). The following explanation provides a background to the Inactive Active Comment P450 nomenclature that accompanies accounts of the me- substance metabolite(s) tabolism of several individual drugs in this book. The metabolic processes 15 An isoenzyme is one of a group of enzymes that catalyse the same The liver is by far the most important drug-metabolising or- reaction but differ in protein structure.
