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By E. Navaras. Central Methodist College. 2018.

Removal of these antagonists from Any given effector tissue probably contains more than the biophase is not sufficient to restore the responsive- one receptor subtype generic 40 mg prednisone, and it is likely that the proportion ness of the effector to agonists order prednisone 5mg. Because of the ap- Nevertheless, the designation of a drug as a selective parently irreversible nature of this drug antagonism, it agent for either a 1-receptor or a 2-receptor seems is termed irreversibly competitive or non–equilibrium both useful and justified if one keeps in mind that the competitive (see Chapter 2). They prevent the agonist from in- recent molecular biological evidence indicates the teracting with its receptor. It is suggested that the 3- receptor may mediate some of the metabolic effects of catecholamines, although no available -blocker has CLASSIFICATION OF BLOCKING DRUGS been shown to rely on 3-receptor antagonism for its An -receptor is one that mediates responses for which therapeutic effectiveness. It follows from this There are differences between the receptors on nerves definition that phentolamine and phenoxybenzamine are (presynaptic receptors) and those on effector cells called -adrenoceptor antagonists or -blocking agents. Furthermore, some -agonists A -receptor mediates responses for which the adreno- and antagonists exhibit selectivity for one of these re- mimetic order of potency is isoproterenol greater than ceptor types. Terminology classifies receptors as either epinephrine greater than or equal to norepinephrine, 1 or 2. Propranolol is, therefore, called a -adrenoceptor receptors of smooth muscle, while 2-receptors are antagonist or -blocking agent. However, the designation of receptors as either 1 or 2 cannot be categorized -Receptor Subtypes strictly by anatomical location (i. Among the responses mediated tors occupy, in addition to peripheral nerves, a variety of by 1-receptors is cardiac stimulation, whereas 2- sites including smooth muscle, adrenal medullary cells, receptor stimulation mediates bronchodilation and re- the brain, and melanocytes. Phentolamine is a disap- three classes of -adrenoceptor antagonists, the quina- pointing antihypertensive drug because its administra- zoline compounds are of greatest clinical utility and are tion results in a reflex increase in both heart rate and con- emphasized in this chapter. The use of the haloalky- tractile force; these effects tend to negate the reduction lamines and imidazolines has diminished in recent years in blood pressure that it produces. Phentolamine is a rel- atively nonselective receptor blocking agent, since in ad- The chief use of these drugs is in the management of pri- dition to blocking postsynaptic -receptors, it will block mary hypertension. Examples of quinazoline -blockers 1 presynaptic -receptors; the latter action enhances re- include prazosin (Minipress), trimazosin (Cardovar), 2 lease of norepinephrine, hence augments cardiac rate terazosin (Hytrin), and doxazosin (Cardura). Blockade of 2-receptors may actually potentiate the cardiac effects of sympathetic Mechanism of Action nerve stimulation. Prazosin, in contrast to phentolamine, The -antagonism produced by prazosin and the other is relatively selective for 1-receptors; that is, it preferen- quinazoline derivatives is of the equilibrium-competi- tially blocks responses mediated by the postsynaptic 1- tive type. The drugs are selective for 1-adrenoceptors, receptors in the blood vessels without having a substan- so that at usual therapeutic concentrations there is little tial effect on presynaptic 2-receptors. While most of the pharmacological ef- does not exist for any available -agonists and antago- fects of prazosin are directly attributable to 1-antago- nists. Furthermore, as is the case with -receptors, a given nism, at high doses the drug can cause vasodilation by a effector tissue may contain more than one -receptor direct effect on smooth muscle independent of -recep- subtype. This action appears to be related to an inhibition of 1-receptors, vascular smooth muscle may possess 2- phosphodiesterases that results in an enhancement of receptors. Prazosin is readily absorbed after oral administration, It is becoming increasingly clear that neither 1- nor peak serum levels occur approximately 2 hours after a 2-receptors are homogeneous. There seem to be at single oral dose, and the antihypertensive effect of pra- least three subtypes of both 1- and 2-receptors, that zosin persists for up to 10 hours. The drug is exten- antagonists can be reasonably well explained by consid- sively (perhaps as high as 97%) bound to plasma pro- ering their relative selectivity for the two main classes of teins; this observation partially explains the lack of cor- -receptors, 1 and 2. Plasma levels of prazosin are in- tage to tamsulosin as an agent for treatment of patients creased in patients with renal failure; the nature of this with benign prostate hypertrophy (discussed later). Pharmacological Actions -RECEPTOR BLOCKING AGENTS The most important pharmacological effect of prazosin is The clinically important -blockers fall primarily into its ability to antagonize vascular smooth muscle contrac- three chemical groups: the haloalkylamines ( e. Hemodynamically, the stimulation of the heart and renin release is less promi- effects of prazosin differ from those of phenoxybenza- nent with this drug. Also, increases in heart rate, contractile force, and plasma Prazosin is effective in reducing all grades of hyper- renin activity, which normally occur after the use of va- tension. The drug can be administered alone in mild sodilators and -blockers, are much less prominent fol- and (in some instances) moderate hypertension. The antihypertensive actions of pra- receptors on nerves and therefore can enhance the re- zosin are considerably potentiated by coadministra- lease of norepinephrine. When norepinephrine exerts a tion of thiazides or other types of antihypertensive postsynaptic action by means of -adrenoceptors (e. Prazosin or when blood pressure is not well controlled by other blocks responses mediated by postsynaptic 1-receptors drugs. Thus, blood uric acid or glucose levels, it can be used in hy- 11 Adrenoceptor Antagonists 113 pertensive patients whose condition is complicated by tic doses, the actions of the -receptor blocking agents diabetes mellitus or gout.

In early 2002 order 20 mg prednisone with amex, several published studies showed conflicting results about the effects of Preparations long-term chronic use of marijuana on memory and cog- Cannabis extracts order prednisone 10mg online, prepared for medicinal application, nitive function. Further research on the smoking, which quickly delivers the active ingredients to effects of marijuana on memory and how long those ef- the blood system. The essential oil consists of beta caryophyllenes, Some people may be hypersensitive to marijuana. Chronic sinus fungal infections have been from the seeds is used for massage and in making salves linked to chronic marijuana smoking. Interactions Precautions Marijauna use may mask the perceived effects of al- Marijauna is considered a Class I narcotic and its cohol and cocaine when the drugs are consumed togeth- use has been restricted by federal law since 1937. Marijuana is said to exert a synergistic effect with ties include fines and imprisonment. When used with nitrous oxide it mission on Marihuana and Drug Abuse concluded in may enhance the effect. Peterson Field Guides, Research has shown that cannabis acts to increase Eastern/Central Medicinal Plants. Early results indicate that pregnant women should nal of the American Medical Association 273, No. GALE ENCYCLOPEDIA OF ALTERNATIVE MEDICINE 2 1291 OTHER Campaign to Legalize Cannabis International Association. Other names for marsh mallow include mallards, mauls, sweetweed, Marsh mallow (Althaea officinalis) is a perennial Schloss tea, and mortification root. Arabian doctors created a poultice from the leaves eastern Mediterranean, and is native to Europe and west- to treat inflammation. Marsh mallow is found in North America along pocrates, used marsh mallow to remedy bruises and the eastern seaboard. Dioscorides wrote about the beneficial prop- erties of marsh mallow, while Horace praised the laxative The plant stems grow to a height of 3-4 ft (1-1. The roots are harvested in the fall, but soothe toothaches, insect bites, indigestion, and diar- the plant must be two years old before the root is harvested. Teething babies The common name marsh mallow is derived from were often given marsh mallow root to provide comfort. The Latin name Al- thaea comes from the Greek word altho, which means to Nineteenth century doctors used the roots of marsh heal or to cure. The family name Malvaceae comes from mallow to make a sore throat lozenge for children and 1292 GALE ENCYCLOPEDIA OF ALTERNATIVE MEDICINE 2 adults. They combined the cooked juice of the root with egg whites and sugar and whipped the mixture into a KEY TERMS meringue that later hardened into a candy. A condition caused by excessive exposure to the Marsh mallow contains starch, mucilage, pectin, oil, cold. It is rich in calcium, zinc, iron, sodium, Decoction—An herbal tea created by boiling iodine, vitamin B complex, and pantothenic acid. Roots, bark, and seeds are used in decoctions; boiling the herbs brings out their medicinal properties. The main therapeutic constituent of marsh mallow is mucilage, a spongy substance of the root that is com- Infusion—An herbal tea created by steeping herbs posed of large sugar molecules. Generally, leaves and flowers are fect stems from its ability to support white blood cells used in infusions. When liquid is added Perennial—A plant that lives for many years; to mucilage, it acquires a gel-like consistency. An infusion can be made by The German Commission E has approved marsh steeping the crushed roots in cold water overnight. The mallow as a beneficial treatment for irritated and in- infusion is then drunk as needed for symptomatic relief. The mixture is covered and leaf are licensed in Germany as standard medicinal teas. The root is also used as an ingredient in cough syrup and as a cough suppressant tea.

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The patient is chal- (C) Physostigmine lenged with edrophonium to evaluate the effective- (D) Neostigmine ness of the cholinesterase inhibition 40 mg prednisone visa. A patient has developed glaucoma that is refractory ing will be indicated by to noncholinergic therapies order 20mg prednisone with amex. A young man broke his leg in a skiing accident, caus- administration of pilocarpine is ing severe muscular spasm that necessitated relax- (A) An increased heart rate ation of the muscle with a competitive nicotinic re- (B) A decreased heart rate ceptor antagonist before the fracture could be set. At (C) Mental confusion the end of the orthopaedic procedure, the doctor re- (D) Constriction of the pupil stored neuromuscular transmission by administering: 132 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM 4. The other preex- (B) Weak atrioventricular conduction isting conditions preclude the administration of (C) Glaucoma AChE inhibitors. Potentiation of parasympathetic (D) Obstruction of the GI tract stimulation can constrict airway smooth muscle and 5. The choice of route of administration plays an im- aggravate asthma, further weaken A-V conduction, portant role in the actions of directly acting choli- and risk perforation of the bowel if an obstruction nomimetics. Hypotension, which can be life threatening, can route of administration is: be avoided by preventing the entry of directly act- (A) Bradycardia ing cholinomimetics into the circulatory system. At an optimal dose of neostigmine, there should SUPPLEMENTAL READING be no change in muscle strength with administra- Abou-Donia M and Lapadula DM. If edrophonium increases organophosphorus ester-induced delayed neurotoxi- muscle strength, the inhibition of AChE is insuffi- city: Type I and type II. A practical guide to strength, the dose of neostigmine is too high, bor- the recognition and management of myasthenia dering on the production of a depolarizing block of gravis. Muscarinic acetylcholine receptors: Signal agonist, will only very transiently increase the transduction through multiple effectors. This will activate sympathetic re- 12 Directly and Indirectly Acting Cholinomimetics 133 Case Study Will you give 2-PAM to Pam? She is sweating The more difficult question is whether oxime treat- profusely, vomiting, and having difficulty breathing. Insecticides can include re- She cannot walk without assistance, and she has a versible carbamate AChE inhibitors or irreversible pulse of 30. Certainly a that the woman had threatened suicide 2 hours ear- quick inquiry to see if the product can be identified lier. Oximes are effective in reactivating AChE inhibited by carbamates as well ANSWER: It is very likely that Pam has ingested an as phosphorylating inhibitors. An addi- treatment does present some risk of its own, and it tional diagnostic test would be to examine the size is not typically used for carbamate poisoning, since of the pupils and test for pupillary reflexes. If it is an the life-threatening stage should pass within a few anti-AChE overdose, the pupils will be constricted, hours. You should immediately prepare for ventila- and they will open only slightly (if at all) when the tory support, as paralysis of the muscles of respira- eye is darkened. So there is no de- atropine, a treatment that typically presents rela- finitive answer to whether to administer an oxime. This will reduce or eliminate many If there is reason to suspect a phosphorylating in- symptoms, including the bradycardia, nausea, hy- hibitor was ingested or the patient is descending potension, sweating, and the component of the res- further into severe respiratory distress, treatment piratory difficulty resulting from bronchoconstric- with an oxime might be warranted. It quate ventilatory support is available, it might be appears that the ingestion occurred in the past 2 better to treat the patient symptomatically. Wonderlin DRUG LIST GENERIC NAME PAGE GENERIC NAME PAGE Atropine 136 Oxybutynin 137 Cyclopentolate 137 Propantheline 137 Dicyclomine 137 Scopolamine 136 Glycopyrrolate 137 Tolterodine 137 Ipratropium 138 Tropicamide 137 Muscarinic blocking drugs are compounds that se- The control of access to muscarinic receptors in the cen- lectively antagonize the responses to acetylcholine tral nervous system (CNS) by a tertiary amine versus (ACh) and other parasympathomimetics that are medi- quaternary ammonium group is fundamentally impor- ated by activation of muscarinic receptors. The belladonna alka- loids, such as atropine, are the oldest known muscarinic MECHANISM OF ACTION blocking compounds, and their medicinal use preceded Antimuscarinic drugs are competitive antagonists of the the concept of neurochemical transmission. The seven trans- membrane helices of these receptors have a ringlike or- ganization in the cell membrane that forms a narrow CHEMISTRY central cleft where ACh binds. At least seven amino The best known of the muscarinic blocking drugs are the acids from four transmembrane helices have been im- belladonna alkaloids, atropine (Atropine) and scopol- plicated in agonist binding to the muscarinic receptors. They are tertiary amines that con- Some of these residues, particularly a negatively tain an ester linkage. Atropine is a racemic mixture of charged aspartate, interact electrostatically with the DL-hyoscyamine, of which only the levorotatory isomer is positively charged quaternary ammonium moiety of pharmacologically active. Atropine and scopolamine are ACh, whereas other residues are required for binding to parent compounds for several semisynthetic derivatives, the ester moiety.

Fomivirsen is contraindicated in patients who have been treated with cidofovir within the previous 2 to 4 Adverse Effects safe prednisone 20mg, Contraindications buy prednisone 20 mg with mastercard, weeks because cidofovir increases the risk of ocular in- and Drug Interactions flammation. Adverse effects include headache, nausea, Foscarnet (Foscavir) is an inorganic pyrophosphate ana- and diarrhea. Confusion may occur, particularly in the logue that acts in vitro against HSV-1, HSV-2,VZV, CMV, elderly. Animal studies have indicated that chronic fam- of viral DNA polymerase and reverse transcriptase by re- ciclovir administration may be tumorigenic and impair versibly binding to the pyrophosphate-binding site of the spermatogenesis. Dosage adjustment is necessary in in- viral enzyme and preventing the cleavage of pyrophos- dividuals with renal impairment. Famciclovir may interact with probenecid or other Resistance to foscarnet may result from mutation of drugs eliminated by renal tubular secretion. Because this drug does not action may result in increased blood levels of penci- require phosphorylation for activation, thymidine clovir or other agents. Fomivirsen Absorption, Metabolism, and Excretion Fomivirsen (Vitravene), an anti-CMV agent, is the first antisense oligonucleotide to be approved by the U. Because of its poor oral bioavailability, foscarnet is ad- Food and Drug Administration (FDA) as an antiviral ministered intravenously. Fomivirsen is an oligonucleotide complemen- sion, 14 to 17% of foscarnet is bound to plasma pro- tary to the major immediate early region 2 (IE2) of teins. By binding to IE2 mRNA, fomivirsen vitreous humor is approximately the same as its plasma prevents its translation to protein and thereby blocks level. Because this mechanism of action is account for its bimodal initial half-life of 4 to 8 hours 50 Antiviral Drugs 573 and prolonged terminal elimination half-life of 45 to hypomagnesemia. Foscarnet is eliminated primarily as un- net is given in combination with agents that can cause changed drug via glomerular filtration and active tubu- mineral imbalances. Ganciclovir and Valganciclovir Clinical Uses Ganciclovir (Cytovene) is an acyclic analogue of 2 de- Foscarnet is indicated for the treatment of CMV retini- oxyguanosine with inhibitory activity toward all her- tis in AIDS patients. Valganciclovir (Valcyte) is that of ganciclovir; these drugs are synergistic when the L-valyl ester prodrug of ganciclovir. Host cell Foscarnet is approved for the treatment of acyclovir- enzymes then perform two additional phosphorylations. Foscarnet has also ration into the growing DNA strand causes chain ter- been used for the treatment of acyclovir-resistant VZV mination in a manner similar to that of acyclovir. However, mammalian bone marrow cells are and Drug Interactions sensitive to growth inhibition by ganciclovir. The most clinically significant adverse effect of foscarnet Resistance to ganciclovir has been found in individ- is renal impairment. Nephrotoxicity is most likely to oc- uals exposed to the drug for long periods and in people cur during the second week of induction therapy but may who have never been treated with this agent. The prin- occur at any time during induction or maintenance ther- cipal mechanism of resistance is mutation of the protein apy. Mutations in the DNA polymerase have to 50% of patients; this effect is usually reversible upon been seen more rarely. Dehydration, previous renal im- pairment, and concurrent administration of other Absorption, Metabolism, and Excretion nephrotoxic drugs increase the risk of renal toxicity. Ganciclovir can be given orally or intravenously; how- Infusion of fluids along with foscarnet decreases the like- ever, its oral absorption is poor (6–9%). Dosage ad- is well absorbed from the gastrointestinal tract and is justment is required for patients with renal insufficiency. The bioavailability Foscarnet is also associated with adverse effects on of ganciclovir following valganciclovir administration is a variety of other organ systems. Following intravenous administra- in serum electrolytes, including hypocalcemia, hy- tion, ganciclovir is found in the vitreous humor at pophosphatemia, hyperphosphatemia, hypomagne- concentrations approximately equal to plasma levels. Neurological and cardiovascu- Ganciclovir is not metabolized appreciably and is elim- lar signs such as paresthesia, tetany, arrhythmias, and inated by glomerular filtration and active tubular secre- seizures may result from these mineral imbalances.

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