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Itiscomplicatedbyanever-increasing awarenessof the final stages (importer cilostazol 100mg without a prescription spasms during bowel movement, wholesaler) quite innocent buy cilostazol muscle relaxant football commercial, so the risks and benefits (real or perceived) of medicines by the well has the process been obscured best order cilostazol muscle relaxant whole foods. Some new medicines are registered with the have inspection and enforcement procedures to detect highexpectation ofeffectiveness and withverylittlesafetyin- and take appropriate action on illegal activities. A patient with obsessive– years to appear with sufficient conviction that causality is ac- compulsive disorder was receiving treatment with olanza- cepted. His custom was rigorously to polish the tablets each pointed out that there is uncertainty in three areas:18 day before consumption. Regula- Complementary and alternative tory authorities are frequently accused of being too cau- tious, and responsible, at least in part, for the stagnation medicine in new drug development. Therefore, although it is part and therapeutic practices; it includes herbal and traditional of the decision-taker’s job to facilitate the doing of good, (mainly Chinese) medicines, homoeopathic remedies and the avoidance of harm looms larger. The efficacy, safety induced by the prospect of finding they have approved a and quality of herbal23 and homoeopathic24 preparations drug that has, or may have, caused serious injury and that have been critically reviewed. They present a serious health (and 22Baber N S 2003 Complementary medicine, clinical pharmacology and economic) problem in countries with weak regulatory therapeutics [editorial]. British Journal of Clinical Pharmacology 18Lord Ashby 1976 Proceedings of the Royal Society of Medicine 69:721. Drugs are commonly categorised appropriate, alternative names in the text and index according to the convenience of whoever is discussing (in brackets). A proprietary (brand) name that is the commercial The proprietary name is a trademark applied to particular property of a pharmaceutical company or companies. It is designed to maximise the difference between the names of similar drugs marketed by rivals for obvious commercial Example: one drug – three names reasons. But, by agreement with the prescribing doctor, they may substitute an ap- The full chemical name describes the compound for chem- proved generic product (generic substitution). Three principles remain supreme and unchallenged in importance:theneedfordistinctioninsoundandspelling, Non-proprietary names especially when the name is handwritten; the need for The principal reasons for advocating the habitual use of freedom from confusion with existing names, both non- non-proprietary (generic) names in prescribing are de- proprietary and proprietary, and the desirability of 3 scribed below. Non-proprietary names give information on the The generic names diazepam, nitrazepam and flurazepam class of drug; for example, nortriptyline and amitriptyline are all of benzodiazepines. Their proprietary names are are plainly related, but their proprietary names, Allegron Valium, Mogadon and Dalmane respectively. Any phar- thinking that different proprietary names must mean differ- maceutical company may manufacture a drug that has a entclassesofdrugs. Suchoccurrencesunderline thewisdom well-established use and is no longer under patent restric- of prescribing generically, so that group similarities are tion, in accordance with official pharmacopoeial quality immediately apparent, but highlight the requirement for criteria, and may apply to the regulatory authority for a li- brand names to be as distinct from one another as possible. The task of authority is to ensure that Relationships cannot, and should not, be shown by brand these generic or multi-source pharmaceuticals are inter- names. Drugs sold under non-proprietary names are cally equivalent, so that a formulation from one source usually, but not always, cheaper than those sold under pro- will be absorbed and give the same blood concentrations prietary names. Pharmacists may supply whatever version they stock,5 whereas if a proprietary name is used they for these well-established drugs. They may licensed product that the dispensing pharmacy has chosen have to buy in the preparation named even though to purchase (on economic criteria; see ‘generic substitu- they have an equivalent in stock. Kluwer Academic, Dordrecht, 5This can result in supply of a formulation of appearance different from pp. A more recent cause for confusion for patients (con- sumers) in purchasing proprietary medicines is the use Proprietary names by manufacturers of a well-established ‘brand’ name that is associated in the mind of the purchaser with a par- The principal non-commercial reason for advocating the ticular therapeutic effect, e. There is substance in this original medicine, the manufacturer aims to establish argument, though it is often exaggerated. This unsavoury practice is called ‘umbrella It is reasonable to use proprietary names when dosage, branding’. In addition, with Formulary provides a regularly updated and comprehensive the introduction of complex formulations, e. There are no absolute rights or clear handwriting is shown by medicines of totally different wrongs in this. Serious events have occurred quires inventions, but wishes a healthy generic market in as a result of the confusion of names and dispensing the order to restrain costs. It will to minimise the risk of confusion, but the use of accepted be noted that non-proprietary names are less likely to be prefixes and stems for generic names works well and the av- confused with other classes of drugs. The search for proprietary names is a ‘major problem’ for 7Pharmaceutical companies increasingly operate worldwide and are pharmaceutical companies, increasing, as they are, their liable to find themselves embarrassed by unanticipated verbal output of new preparations. For example, names marketed (in some countries), such new preparations (not new chemical entities) a year, an- as Bumaflex, Kriplex, Nokhel and Snootie, conjure up in the minds of other warning of the urgent necessity for the doctor to cul- native English speakers associations that may inhibit both doctors and patients from using them (see Jack & Soppitt 1991 in Guide to further tivate a sceptical habit of mind. Knowledge of the requirements for success and the expla- The practice of drug therapy entails more than remember- nations for failure and for adverse events will enable the ing an apparently arbitrary list of actions or indications. Sci- doctor to maximise the benefits and minimise the risks entific incompetence in the modern doctor is inexcusable of drug therapy. Pharmacokinetics • Time course of drug concentration: drug passage across Understanding how drugs act is not only an objective cell membranes; order of reaction; plasma half-life and of the pharmacologist who seeks to develop new steady-stateconcentration;therapeuticdrugmonitoring. The starting point is to consider what drugs do and how Individual or biological variation they do it, i. The body functions • Pharmacogenomics: variability due to inherited through control systems that involve chemotransmitters or influences. Such drugs neither they nor the water in which they are dissolved is are structurally specific in that small modifications to their absorbed by the cells lining the gut and kidney tubules chemical structure may profoundly alter their effect. Mechanisms Receptors An overview of the mechanisms of drug action shows that Most receptors are protein macromolecules. When the ago- drugs act on specific receptors in the cell membrane and in- nistbindstothereceptor,theproteinsundergoanalteration terior by: in conformation, which induces changes in systems within • Ligand-gated ion channels, i. Manykindsofeffectorresponseexist, act on such receptors in the postsynaptic membrane of but those indicated above are the four basic types. When tissues are continuously exposed to the cell membrane and coupled to intracellular effector an agonist, the number of receptors decreases (down-regula- systems by a G-protein. For instance, catecholamines tion) and this may be a cause of tachyphylaxis (loss of effi- (the first messenger) activate b-adrenoceptors through a cacy with frequently repeated doses), e. Indeed, one explanation for modulator of the activity of several enzyme systems the worsening of angina pectoris or cardiac ventricular ar- that cause the cell to act. Drugs that have no activating effect whatever on the used to protect against the nephrotoxic effects of receptor are termed pure antagonists. Some drugs, in addition to blocking ac- penicillin interferes with formation of the bacterial cell cess of the natural agonist to the receptor, are capable of a wall; or by showing enormous quantitative differences low degree of activation, i. A patient may be as extensively ‘b-blocked’ by proprano- Restoration of the response after irreversible binding re- lol as by pindolol, i. The agonist action of benzodiazepines on the benzodiazepine receptor Physiological (functional) antagonism in the central nervous system produces sedation, anxiolysis, muscle relaxation and controls convulsions; substances An action on the same receptor is not the only mechanism called b-carbolines, which also bind to this receptor, by which one drug may oppose the effect of another. Ex- cause stimulation, anxiety, increased muscle tone and treme bradycardia following overdose of a b-adrenoceptor convulsions; they are inverse agonists. If the forces that bind Adrenaline/epinephrine and theophylline counteract drug to receptor are weak (hydrogen bonds, van der Waals bronchoconstriction produced by histamine released from bonds, electrostatic bonds), the binding will be easily and mast cells in anaphylactic shock by relaxing bronchial rapidly reversible; if the forces involved are strong (covalent smooth muscle (b2-adrenoceptor effect). A sufficient in- crease of the concentration of agonist above that of the an- tagonist restores the response. For example, abolish exercise-induced tachycardia, showing that the de- enalapril is effective in hypertension because it is structur- gree of blockade is enhanced, as more drug becomes avail- ally similar to the part of angiotensin I that is attacked by able to compete with the endogenous transmitter.

This action has been best characterized on dopamine-containing substantia nigra neurons cheap cilostazol uk muscle relaxant on cns, where D -receptor activation opens potassium channels via the G2 i coupling protein purchase cilostazol uk back spasms 24 weeks pregnant. Norepinephrine Most noradrenergic neurons are located in the locus caeruleus or the lateral tegmental area of the reticular formation generic 50 mg cilostazol amex spasms on left side of abdomen. This effect is mediated by α receptors and has been2 characterized most thoroughly on locus caeruleus neurons. The indirect mechanism involves disinhibition; that is, inhibitory local circuit neurons are inhibited. Facilitation of excitatory1 synaptic transmission is in accordance with many of the behavioral processes thought to involve noradrenergic pathways, eg, attention and arousal. These neurons project widely throughout the brain and spinal cord where they modulate arousal, attention, feeding behavior, and memory (see Chapter 16). Centrally acting antihistamines are generally used for their sedative properties and antagonism of H1 receptors is a common side effect of many drugs including some tricyclic antidepressants and antipsychotics. The pathways for many of the peptides have been mapped with immunohistochemical techniques and include opioid peptides (eg, enkephalins, endorphins), neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone. Unlike the classical neurotransmitters above, which are packaged in small synaptic vesicles, neuropeptides are generally packaged in large, dense core vesicles. As in the peripheral autonomic nervous system, peptides often coexist with a conventional nonpeptide transmitter in the same neuron, but the release of the neuropeptides and the small molecule neurotransmitters can be independently regulated. Most neuropeptide receptors are metabotropic and, like monoamine receptors, primarily serve modulatory roles in the nervous system. Substance P is contained in and released from small unmyelinated primary sensory neurons in the spinal cord and brainstem and causes a slow excitatory postsynaptic potential in target neurons. These sensory fibers are known to transmit noxious stimuli, and it is therefore surprising that—although substance P receptor antagonists can modify responses to certain types of pain—they do not block the response. Glutamate, which is released with substance P from these synapses, presumably plays an important role in transmitting pain stimuli. Orexins are also called hypocretins because of the near simultaneous discovery by two independent laboratories. In particular, orexin neurons exhibit firing patterns associated with wakefulness and project to and activate monoamine and acetylcholine neurons involved in sleep-wake cycles (see also Chapter 22). In addition to promoting wakefulness, the orexin system is involved in energy homeostasis, feeding behaviors, autonomic function, and reward. These ligands are not stored, as are classic1 neurotransmitters, but instead are rapidly synthesized by neurons in response to depolarization and consequent calcium influx. Although a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial. Nitric oxide diffuses freely across membranes and thus has been hypothesized to be a retrograde messenger, although this has not been demonstrated conclusively. Presynaptic A1 1 receptors inhibit calcium channels and inhibit release of both amino acid and monoamine transmitters. She has tried various over-the-counter sleep remedies, but they were of little help and she experienced “hangover” effects on the day following their use. She drinks decaffeinated coffee but only one cup in the morning; however, she drinks as many as 6 cans per day of diet cola. Assignment of a drug to the sedative-hypnotic class indicates that it is able to cause sedation (with concomitant relief of anxiety) or to encourage sleep (hypnosis). Because there is considerable chemical variation within the group, this drug classification is based on clinical uses rather than on similarities in chemical structure. Anxiety states and sleep disorders are common problems, and sedative-hypnotics are widely prescribed drugs worldwide. A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep. The linear slope for drug A is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death. This appears to be the case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action. All of the structures shown in Figure 22–2 are 1,4- benzodiazepines, and most contain a carboxamide group in the 7-membered heterocyclic ring structure. A substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity. The structures of triazolam and alprazolam include the addition of a triazole ring at the 1,2-position. The chemical structures of some older and less commonly used sedative-hypnotics, including several barbiturates, are shown in Figure 22–3. Glutethimide and meprobamate are of distinctive chemical structure but are practically equivalent to barbiturates in their pharmacologic effects. The sedative-hypnotic class also includes compounds of simpler chemical structure, including ethanol (see Chapter 23) and chloral hydrate. Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine; zaleplon, a pyrazolopyrimidine; and eszopiclone, a cyclopyrrolone (Figure 22–4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon and tasimelteon, melatonin receptor agonists, are newer hypnotic drugs (see Box: Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Box: Buspirone). Other classes of drugs that exert sedative effects include antipsychotics (see Chapter 29), and many antidepressant drugs (see Chapter 30). Certain antihistaminic agents including hydroxyzine and promethazine (see Chapter 16) are also sedating. Other antihistaminic drugs with hypnotic effects, eg, diphenhydramine and doxylamine, are available in over-the-counter sleep aids. Absorption and Distribution The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach.

The sequelae of events after left heart tivity are not sufficiently effective when tubular function failure roughly follow the pattern of reduced stroke vol- has been compromised greatly cheap cilostazol 50 mg with visa muscle relaxant alcohol addiction. Larger than normal ume cheap 50mg cilostazol with mastercard spasms gallbladder, leading to increased end-systolic and diastolic vol- amounts of furosemide are frequently employed purchase cilostazol 50 mg fast delivery spasms cerebral palsy, and ume, which elevates left ventricular end-diastolic pres- thus it is especially important to monitor the patient for 21 Diuretic Drugs 253 excessive volume depletion. Because these compounds are organic acids Acute Renal Failure and are bound to plasma proteins, they reach the lu- minal fluid by secretion. Any disease condition or drug The principal rationale for the use of diuretics in acute that impairs secretion will affect the access of the di- renal failure is to prevent complete renal shutdown. For ease or by drug-induced renal toxicity, the continued example, renal dysfunction may lead to a buildup of production of even a small amount of urine is probably endogenous organic acids that decrease drug secretion important in reducing further kidney tubular damage. It of Pregnancy should now be obvious that in addition to disease and Many women retain fluid during pregnancy and during electrolyte imbalances, the pharmacodynamic handling the last days of the menstrual cycle. Breast fullness and of the diuretics themselves may be a factor in diuretic subcutaneous swelling or puffiness are the most com- resistance. These patients may thus, when present in relatively high concentrations, be vulnerable to ototoxicity or other adverse effects if may produce some expansion of the extracellular fluid larger amounts of the diuretic are employed. Excessive premenstrual edema fre- Compensatory proximal tubular sodium absorption quently responds well to thiazide therapy. Recent expe- may contribute to or be responsible for the resistance rience has diminished enthusiasm for use of any diuret- to loop diuretics. Since the edema of pregnancy is used as an alternative approach to treating diuretic re- sistance once it has been verified that satisfactory Na frequently well tolerated, concerns of compromised uteroplacental perfusion, possible ineffectiveness of di- restriction is being followed and that the drug is being uretics in preeclampsia, and the risk of adverse effects adequately absorbed. Administration of a carbonic an- hydrase inhibitor may be sufficient to enhance Na de- of diuretics on the baby (e. Alternatively, thiazide newborns) have led to diminished routine use of these diuretics may be combined with the loop diuretic to agents in pregnancy. The thi- azidelike diuretic metolazone, which has some proxi- mal tubule effects unrelated to carbonic anhydrase, ap- Resistance to Diuretic Administration pears to be the most effective of the thiazide and Since the effectiveness of many diuretics ultimately de- thiazidelike drugs in this regard. Therefore, one cause of therapeutic failure or apparent patient refrac- Excessively vigorous diuresis may lead to intravascular toriness to diuretics could be the patient’s continued in- dehydration before removal of edema fluid from the gestion of large quantities of NaC1. This is especially Some of the older diuretic drugs were self-limiting; dangerous if the patient has significant liver or kidney that is, prolonged administration resulted in a gradual disease. This problem was cor- trolyte derangement has been achieved, the effect sought rected through the use of intermittent diuretic therapy. Drug Such a program of several days of diuresis followed by dosage, frequency of administration, and Na intake several days of drug withdrawal delayed refractoriness should be adjusted to achieve homeostasis. Either because of Polysal Cutter toxicity or lack of efficacy, these agents are rarely if Lactated Ringer’s (Several) ever used. Most of these solutions contain electrolytes in the following mEq range: sodium (130–150), potassium (4–12), chloride (98–109), bi- carbonate (50–55), calcium (3–5), and magnesium (0–3). The beneficial effect of the sustained (A) Na reduction of blood pressure is due to reduced vascu- (B) K lar resistance. Extracellular volume remains modestly (C) Ca and Mg reduced and cardiac output returns to pretreatment (D) Uric acid levels. Which of the following drugs is an appropriate ini- and is associated with an increased risk of ventricular tial antihypertensive therapy in an otherwise fibrillation and malignant arrhythmias. However, the degree to (B) Triamterene which individual patients are affected varies, though (C) Hydrochlorothiazide chronic administration of even small doses causes (D) Aldactone some K depletion. One is competition of the thiazide class of pulmonary edema, there is often symptomatic relief diuretics, which are weak organic acids, with uric acid within 5 minutes of starting treatment. Serum concentrations of (A) A rapid diuretic effect uric acid are further elevated by the reduced extracel- (B) An increase in venous capacitance lular volume. Diuretic-induced hyperuricemia may (C) A direct effect on myocardial contractility cause acute gouty attacks. Diuretic drugs and the treatment of Detection, Evaluation and treatment of High Blood edema: From clinic to bench and back again. Diuretics in cardiovascular However, thiazide diuretics are a more conservative therapy: The new clinicopharmacological bases that and approved approach for the initial treatment of matter. Metolazone would be expected to be very effec- tive, particularly in combination with a loop diuretic. Case Study Furosemide Resistance A 26-year-old woman with nephrotic syn- (C) Sequestration of furosemide by intraluminal al- Adrome comes to your office because of wors- bumin thereby reducing its inhibition of the ening edema. On physical examination, her blood to the thick ascending limb of Henle’s loop pressure is 120/85 mm Hg, and she has generalized (E) All of the above massive edema (anasarca). In this patient, secretion of loop di- uretics is limited because of reduced renal blood Which of the following factors may contribute to re- flow and accumulation of organic acids in renal in- sistance to furosemide in this patient? In animals, albumin in (B) Reduced active tubular secretion of furosemide the tubular fluid binds furosemide, preventing its ac- by the proximal tubule organic acid secretory cess to the Na-K-2Cl cotransporter. After prolonged mechanism use of furosemide, hypertrophy of the distal tubule epithelial cells occurs, indicating compensatory in- creased reabsorptive capacity. Hemostasis involves Endothelial cells maintain a nonthrombogenic lining in the interplay of three procoagulant phases (vascular, blood vessels. This results from several phenomena, in- platelet, and coagulation) that promote blood clotting to cluding (1) the maintenance of a transmural negative prevent blood loss (Fig. The fibrinolytic system electrical charge, which is important in preventing ad- prevents propagation of clotting beyond the site of vas- hesion of circulating platelets; (2) the release of plas- cular injury and is involved in clot dissolution, or lysis minogen activators, which activate the fibrinolytic path- (Fig. Stasis favors the restriction of thrombus of fibrinogen mediates binding of fibrinogen to the formation to the site of injury. Aggregation of cir- lation are released or become exposed to blood at the culating platelets to those already adherent amplifies site of injury. Ordinarily, unstimulated platelets do not adhere to factor (a mitogen that initiates smooth muscle cell pro- the endothelial cell surface. The platelets change shape and then able a phospholipid surface (platelet factor 3) that along undergo a complex secretory process termed the release with Ca is required for the activation of several clot- reaction. The platelet aggregate becomes a hemostatic platelet granules and activation of platelet phospholi- plug and is the structural foundation for the assembly of pase A2. Inhibition of free thrombin portant for initiating fibrin formation, while the intrin- is the basis of low-dose prophylactic therapy. The dose must be determined on an indi- merals) into serine proteases (designated by roman nu- vidual basis. Heparin is not absorbed after oral admin- meral followed by the suffix -a), and cofactors that istration and therefore must be given parenterally. Intravenous administration results in an almost immedi- Exposure of blood to tissue factors activates the ex- ate anticoagulant effect. The coagulation cascade is capable of tremendous plasma proteins or secreted into breast milk, and it does amplification as the protease reactions progress. Either deficiency in a single clot- by renal excretion of the unchanged drug and its de- ting factor or therapy with the drugs described in this polymerized and desulfated metabolite.

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