Andrew Shennan MB BS MD FRCOG

• Professor of Obstetrics, Maternal and Fetal Research Unit,
• St Thomas?Hospital, London

The primary action of dobutamine is to increase myocardial contractility and cardiac output without significantly increasing the heart rate bacteria pictures effective 250 mg ceftin. The inotropic effect results primarily from direct 1 receptor stimulation in the heart antimicrobial compounds purchase generic ceftin on line, with lesser contributions from 2 receptor activation antibiotics while breastfeeding order genuine ceftin. Because blood pressure effects of this drug are a function of the combination of 1 and 2 receptor activation and 1 receptor blockade treatment for dogs flaky skin buy ceftin 500 mg amex, however bacteria cheap ceftin online master card, some patients may show a greater pressor effect; whereas others may experience a moderate reduction in ventricular filling pressure and peripheral vascular resistance antimicrobial kitchen countertops cheap 250mg ceftin mastercard. Dobutamine is used for short-term treatment of acute myocardial insufficiency resulting from congestive heart failure, myocardial infarction, or cardiac surgery. All catecholamines and certain other drugs, unless specifically modified at the carbon of the side chain, are subject to enzymatic destruction in the gastrointestinal tract. Catecholamines are usually administered systemically by parenteral injection or intravenous infusion. Topical instillation and inhalation are the preferred routes of administration for ocular and respiratory applications, respectively. Selective 2-Adrenergic Receptor Agonists Although isoproterenol and epinephrine are capable of relaxing bronchial smooth muscle, both drugs (especially isoproterenol) can also cause dangerous tachycardia and arrhythmias. These side effects limit the therapeutic use of these drugs and stimulated a search for selective agonists capable of stimulating 2-adrenergic receptors in bronchial and uterine smooth muscle, while having less effect on the 1 receptors of the heart. The centrally acting 2 receptor agonists used to treat hypertension are given orally and are eliminated largely as unchanged drug. Several of the selective 2 receptor agonists are excreted in the urine as conjugates of sulfate or glucuronic acid. The indirect-acting adrenergic agonists must first enter the neuron to evoke the release of the neurotransmitter norepinephrine. A small amount of tyramine in the neuron is oxidized at the carbon to form octopamine. Octopamine, which has only weak adrenergic activity, can be transported into the storage vesicles, where it may act as a false transmitter. Other avenues for the metabolism of these noncatecholamines include p-hydroxylation, N-demethylation, deamination, conjugation in the liver and kidney, or a combination of all these. After neuronal release, a large portion (80% in some cases) of the adrenergic neurotransmitter is returned to the nerve terminal by an active neuronal uptake process. Of the norepinephrine that is actively transported back into the neuron, a large part is actively returned to the storage vesicles from which it can be released again on neuronal stimulation. About 90% of the total endogenous norepinephrine load excreted in the urine is in the form of vanillylmandelic acid and 3-methoxy-4-hydroxyphenylglycol. Several of these products are conjugated to the sulfate or glucuronide before being excreted by the kidney. Exogenously administered catecholamines and endogenous dopamine and epinephrine are transported and metabolized in much the same manner as norepinephrine. The metabolite formed by the combined action of these enzymes is homovanillic acid. Other factors that determine the choice of a drug include the therapeutic effect versus adverse effects profile and pharmacokinetic factors, such as the rate and routes of absorption, duration of action, and metabolic fate. Injected vasoconstrictors and some other adrenergic agonists are also biotransformed and excreted by some of these same pathways. The following section examines all of these therapeutic uses, indicating in each case one or more preferred drugs. An adverse effect associated with the local administration of nasal decongestants is rebound congestion, a chronic swelling of the nasal mucous membranes after the effect of the drugs wears off. Imidazoline derivatives, such as tetrahydrozoline and oxymetazoline, can paradoxically produce drowsiness, comatose sleep with hypotension, and bradycardia. Adrenergic agonists are often used to produce hemostasis for surgery and to enhance local anesthesia. Whether applied topically or administered by injection with or without a local anesthetic, adrenergic agonists can significantly improve visibility in the operative field in certain situations. Because vasoconstriction is temporary, the use of these drugs is no substitute for the adequate surgical control of bleeding. Adrenergic agonists must often be used with special caution during general anesthesia because certain inhalation anesthetics. Currently, the adrenergic agents most useful in the treatment of bronchospastic disease are agonists with selectivity for 2adrenergic receptors because they produce marked bronchodilation with less effect on the heart than nonselective receptor agonists. The selective 2 receptor agonists used for bronchodilation include metaproterenol, terbutaline, albuterol, levalbuterol, pirbuterol, salmeterol, and formoterol. Other long-acting 2-adrenergic receptor agonists are arformoterol, indacaterol, olodaterol, and vilanterol. Ophthalmic Uses the two major ocular indications for adrenergic agonists are for the production of mild mydriasis and the reduction of intraocular pressure. The former is mediated by stimulation of 1-adrenergic receptors in the radial muscle of the eye. Although muscarinic receptor antagonists such as atropine produce a much stronger pupillary dilation, adrenergic agonists are useful because they cause mydriasis without paralyzing the ciliary muscle (cycloplegia). Phenylephrine and hydroxyamphetamine are the principal adrenergic agonists used to produce mydriasis. The mechanisms for the reduction in intraocular pressure by adrenergic agonist drugs are not well elucidated, but several of these drugs seem to reduce the production and enhance the outflow of aqueous humor and are useful in treating wide-angle glaucoma. Treatment of Hypotension and Shock Shock is a condition caused by inadequate tissue perfusion. It is usually associated with a decrease in arterial blood pressure and, if not treated, may quickly lead to multiorgan system failure. Adrenergic agonists may prove useful in restoring blood pressure and in correcting the distribution of blood flow, especially to the vital organs, whenever shock develops under normovolemic conditions. Such drugs are less beneficial in other shock states associated with hypotension, however, because they may impair blood flow to the kidneys and mesenteric organs. In cardiogenic shock, which is most often caused by acute myocardial infarction, the 1-adrenergic receptor agonists should be useful, but the improvement in tissue perfusion and coronary blood flow is often accompanied by increased myocardial oxygen demand. Dopamine has often been used for initial therapy of cardiogenic shock because it causes less generalized vasodilation than typical receptor agonists, increases contractile force in the heart without increasing heart rate, and, through stimulation of dopamine receptors, may improve renal and mesenteric perfusion. Dobutamine, similar to dopamine, can increase the force of myocardial contraction without producing significant changes in heart rate and is also used in patients with heart failure. Treatment of Allergic States Adrenergic agonists, especially epinephrine, are especially useful in reversing the effects of histamine and other mediators associated with allergic reactions. In contrast to the antihistamines, adrenergic agonists are physiologic antagonists, producing responses opposite to the acute effects produced by histamine and associated autacoids. Fulminating disturbances such as anaphylactic shock require a faster absorption of epinephrine than provided by subcutaneous injection, especially if circulation is impaired. With this latter route of administration, there is a considerable risk of precipitating serious cardiac arrhythmias and ventricular fibrillation. Because of the rapid metabolism of epinephrine, reinjection at intervals of 5 to 15 minutes may be required. Subcutaneous administration generally provides the longest duration of action, and intravenous injection provides the shortest. First, they prolong the duration of local anesthesia several-fold and may improve the frequency of successful nerve block. Table 8-4 illustrates the effect of vasoconstrictors on duration of local anesthesia. Second, systemic toxicity of the local anesthetic may be minimized by reducing the peak blood concentration of the anesthetic agent. Third, when anesthetic solutions are given by infiltration, vasoconstrictors tend to reduce blood loss associated with surgical procedures (see Chapter 14). One issue of potential toxicity is the systemic effects of vasoconstrictors after intraoral injection in patients with cardiovascular disease. Some older reports recommend that cardiac patients be given local anesthetics with vasoconstrictors if needed for adequate anesthesia because the benefits of satisfactory pain control were greater than the risks of small amounts of vasoconstrictor. The validity of this statement depends on the level of stress on the patient and the amount, rate, and manner in which the epinephrine-containing solution is injected. It is often necessary to produce gingival retraction for operative procedures on teeth and for making impressions. Besides astringents such as zinc and aluminum salts, retraction cord impregnated with racemic (d and l isomers) epinephrine, containing as much as 1. Racemic epinephrine has approximately half the potency of l-epinephrine because d-epinephrine has approximately one-fifteenth the activity of l-epinephrine. Whether these large amounts of epinephrine present a hazard to a normal patient and to patients with cardiovascular disease depends on several factors. Experimental and clinical studies indicate a relatively high absorption of the vasoconstrictor if the epithelium is abraded or the vasculature is exposed, which is common in extensive restorative procedures. Systemic absorption is marked by signs of anxiety, elevated blood pressure, increased heart rate, and occasional arrhythmias. These effects can be extremely serious in a patient with cardiovascular disease or in a patient who is taking medication that reduces the uptake or otherwise enhances the activity of adrenergic agents. Because of this concern, epinephrineimpregnated retraction cord is used much less often than other types of retraction cord. Various products are available to control capillary bleeding occurring with surgical procedures on gingival tissues. Topical epinephrine hydrochloride (1:1000) and phenylephrine (1:100) are most common. More concentrated solutions have occasionally been recommended, decreased sense of fatigue. Another potentially therapeutic effect of these agents is stimulation of the lateral hypothalamus and satiation of the food drive. Because of the history of abuse of amphetamine-like drugs, their procurement and use are strictly controlled by various state and federal statutes. A major accepted use of amphetamine and related drugs is for the management of children with attention-deficit/hyperactivity disorder. Methylphenidate has been used most often for the pharmacologic treatment of attention-deficit/hyperactivity disorder. It has a relatively brief duration of action (3 to 5 hours), requiring a second dose that often must be administered by teachers or daycare providers. Alternative agents that have gained wider use in recent years include extended duration formulations of methylphenidate or the combination of amphetamine and dextroamphetamine. They act on central 2 receptors that are involved in the autonomic regulation of the cardiovascular system. Generally, these drugs do not reduce sympathetic tone as much as do peripherally acting inhibitors of the sympathetic nervous system or its receptors (see Chapter 9). The vasoconstrictor most commonly used in dentistry is epinephrine, with levonordefrin (the l isomer of nordefrin) being used less frequently, usually with mepivacaine. Table 8-3 lists the concentrations and amounts of adrenergic vasoconstrictors contained in commercially available dental local anesthetic cartridges. The maximum recommended strength of the vasoconstrictor is 1:100,000 epinephrine equivalency for routine nerve block anesthesia. When local tissue hemostasis is required for surgical procedures, such as periodontal surgery, the dentist may additionally choose to infiltrate the area with local anesthetic solution containing 1:50,000 epinephrine, but repeated injections of 2% lidocaine with 1:50,000 epinephrine may cause tissue necrosis and microscarring. The mean and maximum duration of anesthesia was judged by luxation of the tooth and by the use of probes for soft tissue effects. All injections were inferior alveolar nerve blocks; 24 patients were included in each group. Toxic reactions can result from the administration of too large a dose, accidental intravascular injection, impaired uptake of the drug, a heightened sensitivity or number of adrenergic receptors, or therapeutic doses given to a patient with preexisting cardiovascular disease. Relatively small amounts of epinephrine can cause potentially grave effects in a highly susceptible patient. Generally, serious complications may be expected with doses of epinephrine greater than 0. Reviews of the literature indicate that reported adverse reactions attributable to vasoconstrictors used with local anesthetics in dentistry are rare. Most serious of the toxic effects of epinephrine are cardiac disturbances, with increased stimulation of the heart leading to myocardial ischemia, possibly heart attack, and arrhythmias, including ventricular fibrillation. Patients with a history of uncontrolled hyperthyroidism, hypertension, or angina pectoris are particularly susceptible. The increase in blood pressure from rapid parenteral administration can be severe enough to result in hypertensive crisis, which can cause cardiac disturbances or a cerebrovascular accident. Drugs with primarily -adrenergic receptor stimulation can cause excessive vasoconstriction in overdose. Local tissue necrosis may result from any vasoconstrictor injected into a region where ischemia is likely, such as the digits of the hands or feet. The most common side effects of centrally acting 2-agonist antihypertensive agents are dizziness, drowsiness, and xerostomia. A particularly troubling adverse effect of centrally acting 2-agonists is rebound hypertension of serious proportions if these drugs are withdrawn abruptly.

Syndromes

• Cancer
• Myelography
• Do not clean cat litter boxes
• Reduced risk of sudden infant death syndrome (SIDS)
• Injury caused during seizures
• Lower GI bleeding: The lower GI tract includes much of the small intestine, large intestine or bowels, rectum, and anus.
• Abdominal pain

Li+ may cause hypotension and cardiac arrhythmias virus zero reviews 500 mg ceftin with amex, but changes are not usually significant if concentrations remain in the therapeutic range infection rate calculation discount 500 mg ceftin with visa. With continued Li+ therapy antibiotic resistant virus ceftin 500mg online, approximately 4% of patients develop diffuse infection rate in hospitals cheap ceftin 250 mg amex, nontoxic goiters antibiotics vs antibacterial purchase cheapest ceftin. Teratogenic effects sulfa antibiotics for sinus infection buy ceftin overnight delivery, such as cleft palate, deformities of the ear and eye, and cardiac defects are associated with Li+ administration during the first trimester of pregnancy. Simple and convenient methods for measuring Li+ have been sought that do not involve taking blood samples. Although the saliva/plasma Li+ ratio varies considerably from patient to patient, within a single patient, its variability is low. General therapeutic uses Li+ is used for the treatment of mania and as long-term treatment of manic-depressive illness. Initial high (therapeutic) doses are often adjusted downward to maintenance levels, which may partially explain the initial feelings of tiredness. Frequent measurements of Li+ are required to maintain proper plasma concentrations. Patients taking Li+ frequently have a metallic taste that can alter the palatability of food. Polydipsia can also contribute to caries if the patient drinks sugary or acidic beverages to relieve the sensation of dry mouth. Examples have been reported, and anesthesia may persist for up to 18 hours in some cases after typical nerve blocks. Nonsteroidal antiinflammatory drugs may decrease the renal excretion of Li+ and lead to toxic plasma concentrations after several days of combined therapy. In early phases of Li+ therapy, facial spasm and transient facial paralysis, especially of the lower jaw, have occurred. Paradoxically, facial pains associated with cluster headaches may respond to treatment with Li+. Hyperparathyroidism, as a result of lithium therapy, may shift the balance of mandibular bone from cortical bone to more trabecular bone and increased tori. Other Antimanic Drugs Approximately 50% of patients who have mania do not respond to Li+. Characteristics common to many Li+-refractory patients include severe mania mixed with either psychotic episodes or anxiety and a history of rapid cycling. Antipsychotic agents are frequently used to help control the florid excitation and delusions early in treatment, and some atypical antipsychotics have been approved for this use. Carbamazepine, an anticonvulsant discussed in Chapter 12, may be effective in some refractory cases. Carbamazepine has been reserved for patients who do not respond to conventional therapy and may be Implications for dentistry Patients with bipolar disease may have substantial dental pathology. Lithium may induce nephrogenic diabetes insipidus producing hyposalivation in about 70% of patients. Carbamazepine is an inducer of drug metabolism, so the potential for multiple drug interactions is present. Valproic acid (sodium valproate) may also be used for the treatment of mania refractory to Li+. Anticonvulsants can contribute a variety of adverse effects and drug interactions. Amoxapine is listed separately from the other tricyclics because it is a second-generation or atypical antidepressant. Tetracyclic-dibenzo cyclohepta pyrrole Asenapine Saphris Also used in conjunction with antidepressants. Her medical history of schizoaffective disease may be treated with one or more agents that have variable efficacy and the potential for distressing side effects, drug interactions, and orofacial and dental disorders. Although early studies of the combination of antipsychotic drugs and antidepressants led to some manic episodes, newer agents are used to treat this disorder more successfully. Her earlier medications were replaced with newer drugs to produce fewer side effects. However, for her condition, the new medications continue to have the potential for extrapyramidal symptoms but more often different side effects, such as weight gain and sexual dysfunction. Instruct the patient on good oral hygiene, a good diet, and regular dental check-ups with possible fluoride treatment. Her medical therapy may also contribute to drug interactions with vasoconstrictors, sedative drugs, and drugs metabolized by cytochrome P450. Like many psychiatric patients, she struggles with cigarette abuse and its harmful effects. You may elect to treat these patients with smoking cessation agents like nicotine replacement products, bupropion, or varenicline. Placebo-controlled trials suggest that such treatments can help and do not interfere with antipsychotic treatment; however, individual case reports note that varenicline may exacerbate schizophrenic or bipolar symptoms. This patient needs dental therapy and can be treated, but with knowledge of the agents used. Dry mouth, caries, bruxism, oral dyskinesias, periodontal disease, and possible changes in bone formation may need treatment. Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium: Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways, Nat Neurosci. Benzodiazepines and benzodiazepine-like drugs are the most commonly prescribed sleep aids. The 2-receptor agonists clonidine and dexmedetomidine produce sedation and modulate the adrenergic stress response without loss of consciousness. Tizanidine has central muscle relaxant properties in patients with spastic disorders such as cerebral palsy. G is a 60-year-old patient with moderate dental anxiety who presents in your office for multiple dental extractions. Her medical history is significant for hypertension, for which she takes verapamil 40 mg three times a day. After she is feeling less anxious, you accompany her to the dental operatory and begin the procedure. After about an hour, you notice that she is no longer responsive and seems to be unconscious. Pharmacokinetic differences and differences in mechanisms of action often distinguish these agents. As anxiolytics, these drugs reduce the anxiety response; as sedatives, they produce relaxation, calmness, and decreased motor activity * the authors wish to recognize Dr. As hypnotics, they induce drowsiness and a depressed state of consciousness that resembles natural sleep, with decreased motor activity and impaired sensory responsiveness. As anesthetics, these drugs cause a state of unconsciousness from which the patient cannot be aroused. Insomnia is the salient feature of the nearly 90 different forms of sleep disorders. Epidemiologic studies report that insomnia is widespread, affecting one-third of the population. Insomnia is more prevalent among women than men and is more common in elderly individuals than in younger individuals. Benzodiazepine receptor agonists are currently the most commonly prescribed sleep aids. In the United States, approximately 8% of the population has an anxiety disorder during any given 6-month period. Although most individuals have certain periods and degrees of anxiety, pharmacotherapy is indicated only when anxiety begins to interfere with daily life. Similarly, pharmacotherapy should be considered when situational anxiety, such as might be experienced by a patient in anticipation of an operative or diagnostic procedure, is judged to be sufficient to compromise clinical care. These include panic disorder with or without agoraphobia, agoraphobia without panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, acute stress disorder, posttraumatic stress disorder, social phobia, specific (simple) phobia, substance-induced anxiety disorder, and anxiety resulting from a general medical condition. The major emphasis in this chapter is on drugs effective against anxiety as a symptom rather than as a specific disorder. The usefulness and effectiveness of any given antianxiety agent varies depending on the patient, the clinical surroundings, the "chairside" manner of the dentist, the route of administration, and the properties of the chosen drug. Knowledge of the pharmacologic characteristics of the various antianxiety agents is crucial for selecting the proper drug, avoiding drug interactions, and obtaining the desired therapeutic response with minimal adverse side effects. All benzodiazepines currently available in the United States are derived from the basic molecule shown in Table 11-1, to which are added various substituent groups. Triazolam is derived from alprazolam by the addition of a chlorine atom on the ortho position of the phenyl group. Estazolam is formed from alprazolam by removal of the methyl group of the triazolo ring (not shown). The heterogeneity of receptor subunits may offer an explanation for the diverse pharmacologic effects (antianxiety, anticonvulsant, sedative, and skeletal muscle relaxant) of benzodiazepines. Determination of the molecular basis of receptor heterogeneity may eventually facilitate the development of benzodiazepines with a greater degree of selectivity in producing each of these effects. The existence of subclasses of benzodiazepine receptors suggests that some agents, with specific activity for individual receptor subtypes, may be more selective than others in terms of their pharmacologic profile. All benzodiazepines with psychopharmacologic activity have an electronegative group at R7. A chlorine atom seems to confer optimal activity, whereas bromo and nitro substitutions are only weakly anxiolytic. A nitro moiety at R7 enhances antiseizure properties, as illustrated by clonazepam, which is used as an anticonvulsant. Substitution at position 5 with any group other than a phenyl ring also reduces activity. Substitution on the nitrogen at R1 with a methyl group enhances activity, as do methyl or hydrogen groups at R3. Also illustrated is the picrotoxin site, which, when acted on by picrotoxin, antagonizes (minus sign) the influx of Cl- and can lead to convulsions. Multiple receptor subtypes are possible on the basis of different combinations of the subunits. In addition, distinct binding sites for other chemical agents have been identified (shown as blank areas). The figure does not identify which receptor subunits are involved in the binding of each drug. Benzodiazepines previously were thought to differ pharmacologically only in terms of their pharmacokinetics. Alprazolam has documented antidepressant and antipanic properties, and diazepam may be more selective as a skeletal muscle relaxant than other benzodiazepines. Quazepam, a long-acting benzodiazepine hypnotic, produces sedation but seems to have little ataxic effect and may cause less tolerance than other benzodiazepines. Drowsiness and sedation are common manifestations of this central depressant action and may be considered a side effect in some instances and therapeutically useful in others. Differences in their pharmacokinetics may make a given benzodiazepine more suitable as either a hypnotic or an antianxiety agent. Normally vicious macaque monkeys and rats made highly irritable by lesions placed in the septal area of the brain are tamed and calmed by benzodiazepines. The doses required to produce these effects are one tenth of those that cause ataxia and somnolence. Certain benzodiazepines in clinical doses can induce anterograde amnesia, which means that memory of events occurring for a time after drug administration is not retained. This effect is useful therapeutically in intravenous sedation or monitored anesthesia care. These effects are discussed later in this chapter (muscle relaxation) and in Chapter 12 (antiseizure activity). Drug Short-Acting to Intermediate-Acting Alprazolam 1-2 12-15 Estazolam 2 10-24 Lorazepam 1-6 10-18 Midazolam 0. Greater than normal doses decrease blood pressure, cardiac output, and stroke volume in normal subjects and patients with cardiac disease, but these effects are usually not clinically significant. Benzodiazepines are often prescribed for cardiac patients in whom anxiety contributes to their symptoms. Midazolam, used primarily as an oral premedicant, and for intravenous sedation and the induction of anesthesia, can cause respiratory depression and apnea. Absorption, Fate, and Excretion the pharmacokinetics of individual benzodiazepines differ, and there is a wide range in speed of onset and duration of action among these compounds. Benzodiazepines frequently are classified according to their elimination half-life, as illustrated in Table 11-2; however, the elimination half-life of a given drug is only one factor affecting its clinical profile. The rates of drug absorption and tissue distribution and redistribution are often important factors in determining onset and duration of clinical effects after short-term administration. After oral administration, most benzodiazepines are rapidly absorbed and highly bound to plasma protein. A highly lipidsoluble drug such as diazepam exerts its effect more rapidly, whereas lorazepam, which is less lipid-soluble, has a slower onset of action even after systemic absorption. Diazepam also accumulates in body fat because of its lipophilic properties, and it is slowly eliminated from these stores. This characteristic partially accounts for the prolonged half-life of diazepam, which can range from 1 to 4 days. Many benzodiazepines are converted to pharmacologically active metabolites that have long half-lives. Clorazepate and prazepam are nearly completely converted (in the stomach and liver) to the long-acting metabolite desmethyldiazepam (nordazepam) before they enter the systemic circulation.

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Additive or synergistic activity occurs primarily in analgesic circuits resulting in increased opioid analgesic efficacy and potency antimicrobial agents 1 buy ceftin online now. Importantly virus 68 in michigan buy ceftin 500mg lowest price, increased analgesic actions also result in increased safety as lower doses are less likely to produce undesirable side effects infection knee 250 mg ceftin overnight delivery. This knowledge can be used to improve pain control and limit the incidence or severity of undesirable opioid effects triple antibiotic ointment buy discount ceftin on-line. Likewise antibiotics for uti in babies purchase 500mg ceftin with amex, tricyclic antidepressants that block the reuptake of norepinephrine are also effective adjuvants that are used for the treatment of chronic antibiotic resistance latest news buy generic ceftin 250 mg online, but not acute, pain. This strategy allows reduction of the dose of opioid without compromising the analgesia produced (an "opioid-sparing" effect). Two drugs in particular, tramadol and tapentadol, produce analgesic actions by agonist activity at opioid receptors plus inhibition of neuronal reuptake of norepinephrine (tapentadol) and serotonin (tramadol). By requiring less opioid for adequate pain control, undesirable opioid effects, such as urinary retention, respiratory depression, sedation, and development of analgesic tolerance, can be reduced. The cellular mechanisms by which opioids produce their effects are best established for direct actions at opioid receptors located on neurons. Actions commonly produced at all three opioid receptors include inhibition of adenylyl cyclase, inhibition of Ca2+ conductance, activation of K+ conductance, and inhibition of neurotransmitter release. Opioid receptor binding postsynaptically hyperpolarizes the neuronal membrane, which decreases the probability of the generation of an action potential in response to excitatory input at "L" (such as during pain transmission). Activation of the rectifying K+ conductance produces a relative hyperpolarization of neurons, making them more resistant to excitation. All opioid analgesics share with morphine the ability to produce analgesia, respiratory depression, constipation, gastrointestinal spasm, antitussive actions, and physical dependence. Consequently, morphine is discussed in greater detail, and what is stated for morphine applies in general to other opioid agonists. The analgesia produced by morphine and other agonists occurs without loss of consciousness; thus opioids are not suitable for anesthesia. When opioids are administered for relief of pain (or for cough or diarrhea), they provide only symptomatic relief without alleviation of the cause of the pain (or cough or diarrhea). The analgesia produced by opioid analgesics is dose-dependent and selective in that other sensory modalities. The standard parenteral (oral) analgesic dose of morphine, 10mg (30mg)/70kg of body weight, is considered a therapeutic dose for relief of moderate to severe pain. Pain is a highly subjective and personal experience that is influenced by many factors. It is generally accepted that opioid-induced analgesia involves both sensory-discriminative and motivational-affective components of pain. However, opioids preferentially modulate the motivational-affective (aversive) qualities of pain. The sensory-discriminative component of pain is associated with identification and localization of the source and intensity of pain, whereas the motivational-affective component of pain is related to the perception of unpleasantness of the pain. Pain is not a simple sensation associated with a single neuronal circuit, but rather, it is a complex experience that can be influenced by the context in which the pain arises; prior experience and expectation; attention, anxiety, mood, and stress levels; and other societal, emotional, and cognitive contributions. As noted earlier, the nociceptive component (sensation) of pain is generally unaffected by systemically delivered opioid analgesics, a feature that allows these drugs to be used relatively safely. A common report from patients after receiving an opioid for relief of pain is that the pain is still present but that it is not discomforting. Morphine and its congeners depress respiration (tidal volume and rate) in a dose-related fashion. Respiratory depression represents the principal potentially life-threatening effect of opioids. In humans, morphine decreases the response of brainstem respiratory centers to carbon dioxide tension of the blood and depresses pontine and medullary centers that regulate respiratory frequency. Opioids directly stimulate the chemoreceptor trigger zone in the medulla and can produce vomiting (emesis). Opioids are commonly given before, during, and after surgery, and nausea and vomiting are highly undesirable. After the initial period of stimulation, however, opioids depress the brainstem medullary center for vomiting. This subsequent depression occurs at therapeutic concentrations and is virtually total. There is also a vestibular component to the nausea produced by morphine and its congeners because nausea occurs more frequently in ambulatory than in recumbent patients. All currently available opioid analgesics are capable of depressing respiration in a manner similar to that of morphine when administered in doses that produce equal analgesia (exceptions are analgesics that have a nonopioid, as well as opioid, mechanisms of analgesic action). Morphine and other agonists are effective antitussives; codeine is widely used in cough preparations for this purpose. Opioids exert their antitussive effect by depressing an area in the brainstem that mediates the cough reflex. Although the brainstem sites for the respiratory depressant and antitussive effects of opioids are anatomically close, there is no apparent relationship between opioid depression of one or the other because suppression of the cough reflex occurs at opioid doses lower than those required to produce an analgesic effect or to depress respiration. At therapeutic doses, morphine and most of its congeners produce pupillary constriction (miosis) in humans. The miosis produced by opioids results from a central effect mediated by the oculomotor nerve and not from a direct action on the circular or radial muscles of the iris of the eye. Although tolerance to opioids has not yet been discussed, it is appropriate to indicate here that tolerance to the pupillary-constricting effect of morphine and some other opioids does not develop to any appreciable extent. Consequently, Peripheral pharmacology Morphine exerts important indirect influences on smooth muscle tone that have therapeutic and toxic implications. The drug can affect gastrointestinal activity by reducing glandular secretions and by promoting net absorption of fluid from the gastrointestinal lumen. The use of opium for relief of diarrhea and dysentery may have antedated the use of opium for relief of pain. Opioids exert significant effects on smooth muscle all along the gastrointestinal tract; these effects are indirect and mediated by actions on nerves intrinsic to the gut (intrinsic innervation) as well as on nerves innervating the gut from the brainstem and spinal cord (extrinsic innervation). Constipation elicited by long-term opiate exposure can reach such a point as to be intolerable by patients who discontinue the use of opioids in spite of adequate analgesic efficacy. Opioid analgesics can act at opioid receptors on the intrinsic neuronal network in the gastrointestinal tract to inhibit motility. Endogenous opiate peptides have been identified in myenteric neurons and opiate receptors have been localized at presynaptic and postsynaptic sites of the enteric neuronal (myenteric and submucosal) plexus. Thus opiates can inhibit the firing of secretomotor and submucosal neurons as well as inhibit the release of transmitter from these neurons. Opioids may also exert a direct effect via opiate receptors expressed on smooth muscle cells. In the large intestine, muscle spasms can result from the marked increase in muscle tone and nonpropulsive muscle contractions. Spasm of the smooth muscle of the biliary tract can occur after the administration of therapeutic doses of morphine and related drugs, which can be very painful. Morphine and other opioids inhibit relaxation of the sphincter of Oddi in part by enhancing sympathetic tone, which suppresses the activity of inhibitory neurons that mediate relaxation of the sphincter. In addition, gastric acid secretion is usually depressed, and pancreatic, biliary, and intestinal secretions are routinely depressed by opioid administration. Combined inhibition of intestinal fluid secretion and enhancement of absorption are important contributors to the beneficial effect of morphine in the treatment of diarrhea. Morphine and other opioid agonists also increase muscle tone in smooth muscle of the ureters, urinary bladder, uterus, and bronchioles, but at therapeutic doses the effect of opioids on these muscles is generally unremarkable. Urinary retention, characterized by urgency and increased tone of the bladder sphincter, is common after all routes of opioid administration. In addition to effects on tone and contractility of smooth muscle, opioids also possess antidiuretic effects. Although opioids increase uterine tone, they do not generally influence the duration of labor. Likewise in the bronchial musculature, opioids administered at usual therapeutic doses do not produce significant bronchoconstriction, even though they may aggravate an asthmatic condition or precipitate an asthmatic attack resulting in part from stimulation of histamine release. The effects of morphine and other opioid agonists on blood pressure, heart rate, and cardiac work are generally minor at analgesic doses. The vasomotor center of the medulla is relatively unaffected by opioid analgesics, and blood pressure is maintained near normal even after intoxicating doses of opioids. A decrease in blood pressure observed during acute opioid intoxication is primarily caused by hypoxia that results from opioid-induced respiratory depression. Morphine and several other opioid analgesics release histamine and produce some vasodilation of the peripheral vasculature, often resulting in an overall sensation of warmth accompanied occasionally by itching on the face and nose. Mast cell degranulation and histamine release does not appear to be mediated by opioid receptors, but rather, it may be influenced by the chemical properties of individual compounds. For example, morphine produces significant histamine release, whereas fentanyl does not. The resultant decrease in peripheral resistance is the primary cause of the orthostatic hypotension and fainting that occur occasionally in some recumbent patients when the head-up position is suddenly assumed. Opioids have no direct effect on the vasculature and circulation of the brain, but cerebral vasodilation is a common consequence of opioid administration. Cerebral vasodilation is considered to be a consequence of the respiratory depression produced by morphine and its congeners and the subsequent retention of carbon dioxide in the blood. The result is an increase in cerebrospinal fluid pressure, which requires that opioids be used cautiously in cases of cranial trauma and head injury, where cerebrospinal fluid pressure may already be elevated. Morphine is also occasionally used in the treatment of pulmonary edema, where it is quite effective. The mechanism by which morphine exerts this beneficial action is unclear, but morphine seems to inhibit adrenergic tone centrally, promoting redistribution of blood to the periphery and reducing pressure in the pulmonary veins and capillaries without causing concomitant reduction of systemic arterial pressure. Acute opioid intoxication Death from acute intoxication by an opioid analgesic is the result of direct respiratory depression. The cardinal signs of acute opioid intoxication (overdose) represent an extension of the pharmacologic features of these drugs: stupor, constricted pupils, and depressed respiration. As the severity of intoxication increases, coma ensues, and the blood pressure, initially maintained close to normal, steadily decreases if the hypoxia associated with the respiratory depression is unaltered. More recent studies point to neuroplastic changes in the neuraxis as underlying the tolerance to the analgesic action of opioids. Clinical studies have shown that patients with persistent exposure to opiates show enhanced sensitivity to painful stimuli, even while the opiate is still present in the body. Persistent exposure to opioids may cause an increase in release of excitatory neurotransmitters from primary afferent terminals in the spinal cord and trigeminal ganglion, thus enhancing nociceptive inputs. Collectively, these mechanisms amplify the transmission of nociceptive inputs to the brain. This increase in "gain" contributes to the requirement for increased doses of opioids to produce inhibition and to offset the augmented pain. Importantly, this state of amplified signaling can persist so that later insults, such as surgical incision, produce an exaggerated painful response. These amplification mechanisms may also contribute to findings that preoperative loading doses of opioids fail to reduce the postoperative requirement for analgesics, and they can actually increase the need for pain relief. Activation of the mechanisms driving hyperalgesia might be "buried" within the analgesic activity of the opioid, but it is unmasked once the analgesic effect has terminated. Hypoxia precedes death in the absence of alteration in the respiratory status of an intoxicated individual. Restoration of ventilation is most rapidly and dramatically achieved by administration of an opioid receptor antagonist. Restoration of adequate pulmonary ventilation prevents the hypoxic cardiovascular sequelae of opioid intoxication. Although the details of opioid antagonists have not yet been discussed, it is important to interject two notes of caution regarding their use in cases of opioid intoxication. First, the duration of action of naloxone, the standard opioid receptor antagonist, is shorter than that of most opioid analgesics. Consequently, an opioid-intoxicated individual typically requires continued monitoring and readministration of additional naloxone as necessary. Second, administration of an opioid receptor antagonist to an acutely intoxicated, opioid-dependent individual can precipitate a withdrawal syndrome that cannot readily be attenuated during the period of action of the antagonist. Tolerance Tolerance is an observed decrease in effect of a drug as a consequence of prior administration of that drug. Hence, increasingly greater doses of drug must be administered over time to maintain an effect equivalent to the effect produced on initial administration. Generally, tolerance develops to the depressant effects of opioids but not to the same extent to the stimulant effects. Tolerance develops to opioidinduced analgesia, euphoria, drowsiness, and respiratory depression but not to any appreciable extent to opioid effects on the gastrointestinal tract or the pupil. In the therapeutic setting, the initial indication that tolerance has developed is generally reflected in a shortened duration or reduced analgesic effect. The rate at which tolerance develops is a function of the dose and the frequency of administration. Although some patients remain normally sensitive, most patients treated for 5 to 7 or more days exhibit tolerance to the analgesic (and other) effects of opioids. Generally, the greater the opioid dose and the shorter the interval between doses, the more rapidly tolerance develops. Tolerance can develop to such an extent that the lethal dose of the opioid is increased significantly. For any individual, however, there always exists an opioid dose capable of producing death by respiratory depression, regardless of the extent to which tolerance has developed. The mechanisms by which tolerance develops to opioids are not fully known, and many different hypotheses have been proposed.

Diseases

• Glioblastoma
• Kifafa seizure disorder
• Rasmussen Johnsen Thomsen syndrome
• Brachman-de Lange syndrome
• Dandy Walker malformation with mental retardation, macrocephaly, myopia, and brachytelephalangy
• Neuroectodermal tumors primitive
• Muscular dystrophy, congenital, merosin-positive
• Hypoplasia hepatic ductular
• Panthophobia
• Hepatic cystic hamartoma