By N. Grompel. North Carolina Wesleyan College.
NSAIDs can decrease the clearance of have toxicities cheap ampicillin 250 mg otc homeopathic antibiotics for sinus infection, are highly protein bound and have the methotrexate ampicillin 500mg low cost antibiotics pseudomonas, resulting in severe hematological and GI potential for interacting with other protein-bound toxicity. The choice of a particular agent often depends on with low-dose methotrexate used in the treatment of the reaction of the patient. NSAIDs, when used in conjunc- Salicylates tion with immunosuppressive agents, can mask fever and other signs of infection. Only Because NSAIDs decrease prostaglandin synthesis observations that are relevant to their use as anti- in the kidney, these drugs can increase the nephrotox- inﬂammatory agents are discussed in this chapter. E, enterohepatic cycling; F, extensive ﬁrst pass metabolism; h, dosage ad- justment may be necessary in patients with hepatic impairment; H, dosage adjustment recommended for patients with hepatic impairment; R, dosage adjustment necessary for patients with renal impairment. The most common adverse effects produced by the The salicylates are useful in the treatment of minor salicylates are GI disturbances. Occult blood loss from musculoskeletal disorders such as bursitis, synovitis, the GI tract, peptic ulceration, and rarely, severe GI tendinitis, myositis, and myalgia. They can be used in the bound to plasma proteins, it may be displaced by other treatment of inﬂammatory disease, such as acute rheu- highly protein-bound drugs such as oral anticoagulants, matic fever, rheumatoid arthritis, osteoarthritis, and cer- sulfonylureas, phenytoin, penicillins, and sulfonamides. However, effects on blood loss and produce fewer adverse GI other NSAIDs are usually favored for the treatment of effects. In addition, they may be somewhat kidney spar- these chronic conditions because of their lower inci- ing. The use of aspirin in conjunction with any other NSAID is not rec- Basic Pharmacology ommended because of the lack of evidence that such Aspirin is available as capsules, tablets, enteric-coated combinations increase efﬁcacy and because of the in- tablets (Ecotrin), timed-release tablets (ZORprin), creased potential for an adverse reaction. Salicylates are buffered tablets (Ascriptin, Bufferin), and as rectal sup- contraindicated in children with febrile viral illnesses positories. Aryl and Heteroarylakanoic Acid–Type Drugs Although aspirin itself is pharmacologically active, it is rapidly hydrolyzed to salicylic acid after its absorp- The prototypes of this large class of NSAIDs are in- tion, and it is the salicylate anion that accounts for most domethacin and ibuprofen. The supe- for the relief of acute and chronic rheumatoid arthritis rior analgesic activity of aspirin compared with sodium and osteoarthritis. In addition, a number of drugs of this salicylate implies that aspirin has an intrinsic activity class are also useful in ankylosing spondylitis, acute that is not totally explainable by its conversion to sali- gouty arthritis, bursitis, and tendinitis. Aspirin inhibits COX-1 to a much greater ex- Adverse reactions are common with the use of these tent than COX-2; sodium salicylate is more selective for drugs but usually do not result in serious morbidity. The selectivity for COX-1 and COX-2 varies The binding of salicylic acid to plasma proteins from drug to drug and accounts for some of the differ- varies with its plasma concentrations. None of the agents seems to be clearly acid concentrations of less than 100 g/mL, 90 to 95% more efﬁcacious than the others; however, they generally is protein bound; at 100 to 400 g/mL, 70 to 85% is pro- cause less GI blood loss and fewer other adverse reac- tein bound; and at concentrations greater than 400 tions than does aspirin, and the overall incidence of ad- g/mL, 20 to 60% is protein bound. At these higher Indomethacin (Indocin) is used in the treatment of concentrations, salicylate metabolism is reduced, result- acute gouty arthritis, rheumatoid arthritis, ankylosing ing in a longer half-life for the drug. It is not recommended consequence of the saturable enzyme systems that me- for use as a simple analgesic or antipyretic because of its tabolize salicylates. While indomethacin inhibits both has been estimated to be 3 to 6 hours at the lower (anal- COX-1 and COX-2, it is moderately selective for COX- gesic) dosage and 15 to 30 hours at the higher (anti- 1. Severe headache occurs in 25 to 50% of to salicylic acid is not dose limited, and no differences in patients; vertigo, confusion, and psychological distur- the absorption of aspirin have been observed between bances occur with some regularity. The most common adverse reac- effects (blurred vision, corneal deposits) have been ob- tions are GI disturbances and headache. A reversible el- served in patients receiving indomethacin, and regular evation of serum transaminases occurs in 15% of pa- ophthalmological examinations are necessary when the tients. Ibuprofen (Advil, Motrin) is used as an analgesic and antipyretic as well as a treatment for rheumatoid Sulindac arthritis and degenerative joint disease. The most fre- Sulindac (Clinoril) is chemically related to in- quently observed side effects are nausea, heartburn, domethacin and is generally used for the same indica- epigastric pain, rash, and dizziness. The incidence of these effects decreases platelet aggregation, but the duration is is lower than for indomethacin, presumably because shorter and the effect quantitatively lower than with as- sulindac is a prodrug and thus the active metabolite is pirin. As with normal value and should be used with caution in pa- indomethacin, a rather high incidence of CNS side ef- tients who have coagulation deﬁcits or are receiving an- fects (dizziness, headache) also occurs. Tolmetin Fenoprofen Tolmetin (Tolectin) is indicated for the relief of os- Fenoprofen (Nalfon) is chemically and pharmaco- teoarthritis, rheumatoid arthritis, ankylosing spondylitis, logically similar to ibuprofen and is used in the treat- and moderate pain.
The bio- statistical probability of this event is logical effect of the agonist buy ampicillin 500 mg overnight delivery best antibiotics for acne reviews, i ampicillin 250mg visa bacteria jobs. Some agonists attain a maximal conformation, thus promoting its exis- effect even when they occupy only a tence. The “antagonist” displays affinity small fraction of receptors (B, agonist only for the inactive state and stabilizes A). When the system shows min- equal affinity for the receptor but lower imal spontaneous activity, application activating capacity (lower intrinsic ac- of an antagonist will not produce a mea- tivity), are unable to produce a full max- surable effect. When the system has imal response even when all receptors high spontaneous activity, the antago- are occupied: lower efficacy. The potency of an ago- posite of that of the agonist:inverseago- nist can be expressed in terms of the nist. According to this model, a partial ago- Competitive antagonists possess nist shows lower selectivity for the ac- affinity for receptors, but binding to the tive state and, to some extent, also binds receptor does not lead to a change in to the receptor in its inactive state. When an agonist and a competitive Other Forms of Antagonism antagonist are present simultaneously, affinity and concentration of the two ri- Allosteric antagonism. The antagonist vals will determine the relative amount is bound outside the receptor agonist of each that is bound. Thus, although the binding site proper and induces a de- antagonist is present, increasing the crease in affinity of the agonist. It is also concentration of the agonist can restore possible that the allosteric deformation the full effect (C). However, in the pres- of the receptor increases affinity for an ence of the antagonist, the concentra- agonist, resulting in an allosteric syner- tion-response curve of the agonist is gism. The agonist binds to the inactive recep- tor and thereby causes a change from the resting conformation to the active state. The antagonist binds to the inac- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Drug-Receptor Interaction 61 Agonist Antagonist Antagonist Agonist Rare spontaneous transition Receptor inactive active Agonist Antagonist Antagonist Agonist induces active occupies receptor selects inactive selects active conformation of without con- receptor receptor receptor protein formational change conformation conformation A. Molecular mechanisms of drug-receptor interaction Receptors Increase in tension Agonist A Receptor occupation EC50 EC50 Concentration (log) of agonist smooth muscle cell Agonist B Potency B. Potency and Efficacy of agonists Agonist effect 0 1 10 100 1000 10000 Concentration of antagonist Agonist concentration (log) C. Competitive antagonism Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. The mode of attachment at the a molecule and its corresponding mirror receptor also determines whether an ef- image which, like the left and right fect is elicited and whether or not a sub- hand, cannot be superimposed. Usually, (-) dobutamine is an agonist at "-adren- chirality is due to a carbon atom (C) oceptors whereas the (+)-enantiomer is linked to four different substituents an antagonist. Enantiomerism is Inverse enantioselectivity at an- a special case of stereoisomerism. An enantiomer may chiral stereoisomers are called diaster- possess an unfavorable configuration at eomers (e. In the case of dobutamine, the Therefore, enantiomers possess similar (+)-enantiomer has affinity at! As a result of enzy- stimulant action is due to the (-)-form matic activity, however, only one of the (see above). As described for receptor interac- In solution, enantiomers rotate the tions, enantioselectivity may also be wave plane of linearly polarized light manifested in drug interactions with in opposite directions; hence they are enzymes and transport proteins. Enan- refered to as “dextro”- or “levo-rotatory”, tiomers may display different affinities designated by the prefixes d or (+) and l and reaction velocities. The direction of ro- Conclusion: The enantiomers of a tation gives no clue concerning the spa- racemate can differ sufficiently in their tial structure of enantiomers. The abso- pharmacodynamic and pharmacokinet- lute configuration, as determined by ic properties to constitute two distinct certain rules, is described by the prefix- drugs. In some compounds, desig- nation as the D- and L-form is possible by reference to the structure of D- and L-glyceraldehyde. For drugs to exert biological ac- tions, contact with reaction partners in the body is required.