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Biotransformation is the metabolic conversion of drugs buy cialis 20 mg line erectile dysfunction daily pill, generally to less active compounds but sometimes to iso-active or more active forms cialis 2.5mg generic experimental erectile dysfunction drugs. The transformations include hydroxylations and dealkylations cheapest cialis erectile dysfunction viagra does not work, as well as the promotion of oxidation/reduction reactions. The conjugation may be glucuronidation, acetylation, sulfation, or addition of glutathione. I Modes of drug elimination are biotransformation, renal excretion, and excretion by other routes (e. Renal clearance (C1 ) represents the volume of blood cleared by the kidney per unit time and is a R I constant for drugs with first-order elimination kinetics. The time to reach a I steady state is dependent only on the elimination half-life. It is independent of dose and frequency of , administration or rate of infusion (see Figures 1-1-12,-13, and -14). Agonist: A drug is called an agonist when binding to the receptor results in a response. Antagonist: A drug is called an antagonist when binding to the receptor is not associated with a response. The drug has an effect only by preventing an agonist from binding to the receptor. Plots of dose (or log dose) versus response for drugs (agonists) that activate receptors can Definitions reveal information about affinity, potency, and efficacy of these agonists. Affinity is inversely related to Parallel and Nonparallel D-R Curves the Kd of the drug. V Log Dose of Drug Efficacy: the maximal effect Log Dose of Drug an agonist can achieve at the highest practical concentration. Comparison of D-R,Curves for Two Drugs Acting Notice the analogy with the on the Same (left panel) and on Different Vmax used in enzyme kinetic (right panel) Receptors studies. When two drugs interact with the same receptor (same pharmacologic mechanism), the D-R curves will have parallel slopes. In terms of potency, drug A has greater potency than drug B, and X is more potent than Y. Full and Partial Agonists Full agonists produce a maximal response-they have maximal efficacy. Partial agonists are incapable of eliciting a maximal response and are less effectivethan full agonists. In Figure 1-2-2, drug B is a full agonist, and drugs A and C are partial agonists. Efficacy and Potency of Full and Partial Agonists Drug A is more potent than drug C, and drug B is more potent than drug C. However, no general comparisons can be made between drugs A and B in terms of potency because the former is a partial agonist and the latter is a full agonist. At low responses, A is more potent than B,but at high responses, the reverse is true. Pharmacodynamics Duality of Partial Agonists • In Figure 1-2-3, the lower curve represents effects of a partial agonist when used alone-its ceiling effect = 50% of maximal in this example. Duality of Partial Agonists The upper curve shows the effect of increasing doses of the partial agonist on the maximal response (100%) achieved in the presence of or by pretreatment with a full agonist. As the partial agonist displaces the full agonist from the receptor, the response is reduced-the partial agonist is acting as an antagonist. Antagonism and Potentiation • Graded dose-response curves also provide information about antagonists-drugs that interact with receptors to interfere with their activation byagonists. D-R Curves of Antagonists and Potentiators Competitive antagonists are analogous to competitive inhibitors; they decrease Pharmacologic antagonism (same receptor) affinity (I ~) but not - Competitive antagonists: maximal response 0Jmax o Cause a parallel shift to the right in the D- R curve for agonists remains the same). Steep D-R curves reflect little variability; flat D-R curves indicate great variability in patient sensitivity to the effects of a drug. From the data shown, T1 = 10/2 = 5 Such indices are of most value when toxicity represents an extension of the pharmaco- logic actions of a drug. Binding of hormones or drugs to such receptors releases regulatory proteins that permit activation and in some cases dimerization of the hormone-receptor complex. For example, drugs interacting with glucocorticoid receptors lead to gene expression of proteins that inhibit the production of inflammatory mediators.

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Criticsofthis classification systempointout that antiarrhythmic drugs oftencause mixed effects on the cardiaccell and that antiar- rhythmic drugs in the sameVaughan-Williams group can discount cialis master card erectile dysfunction protocol scam or not, clinically speaking safe cialis 5mg erectile dysfunction keeping it up, behave quite differently from oneanother discount cialis 5mg mastercard erectile dysfunction lifestyle changes. The most im- portant confounding variable relates to how antiarrhythmic drugs affectsodium and potassium channels. The binding characteristics of the sodium-blocking drugs, for in- stance, are complex. Although all Class I drugsbind to the sodium channel, they do not bind tonically (i. Actual blockade of the sodium channel (and thus slowing of depolarization)occurs only ifadrug isbound to the sodium channel at the time the channel first opens. How- ever, many Class I drugsbind to the sodium channel only after it has alreadyopened (i. The solid lines represent the baselineactionpotential; dotted lines represent the changes that result when various classes of an- tiarrhythmic drugs are given. There- fore, the effect of a Class I drug on the sodium channel dependson its binding kinetics—the rate at which that drug bindstoand un- binds from the sodium channel (or alternatively, its effect depends on how“sticky” the drug isonce itbindstothechannel; Figure 2. Panels (a) through (e) illustrate the effectoflidocaine, a drug with rapid kinetics. Panels (f) through(j) illustrate the effectofflecainide, a drug with slow kinetics. Panels (f) through (h) show reactions identical to those in panels (a) through(c). At faster heart rates, drugssuchaslidocaine have less timetounbind and can behave more like flecainide. Drugs with rapid binding kinetics therefore produce rel- atively little reductioninconduction velocity. Ingeneral, the slower the binding kineticsofasodium-blocking drug, the more effect the drug has onconduction velocity. To further complicate the issue, the effect of Class I drugson the sodium channel is partially situational. All Class I drugs, for instance, display use dependence: at faster heart rates, the sodium-channel block increases. Use dependence issimply a result of binding kinetics, which reflects that at faster heart rates, there is less time for the drug to unbind from the sodium channel before the next actionpotential begins; thus, at faster heart rates, the drugs have a more profound effectonconduction velocity than they have at slower heart rates. In addition, ischemia, hyperkalemia, and acidosis can slow the binding kinetics of Class I drugsand thus increase the effectofthedrugson the sodium channel. The Vaughan-Williams classification system accounts for the bind- ing kinetics of the sodium-blocking drugs. Although no classification systemislikely to neatly charac- terize the nuances of sodium binding for every drug, the Vaughan- Williams system offers reasonably accurate generalizations about sodium-binding properties of antiarrhythmic drugs. The Vaughan-Williamsscheme is more challengedwhen one be- ginstoconsider the effectofantiarrhythmic drugson the potassium channel. As a result, application of the Vaughan-Williams system becomes very difficult in some cases. Ultimately, the classification of some drugsappears to be a matter of consensus rather than a matter of science. Although the Vaughan-Williamsschemethusappears incapable of offering definitive classification for all possible mixtures of sodium- and potassium-channel blockade, it nonetheless suggests a frame- work for characterizing evendifficult-to-classify drugs. The frame- work becomes apparent when onethinks of the general interplay of sodium-blocking and potassium-blocking properties as represent- ing a continuum of possible effects instead of a categorical series of discrete effects (Figure 2. The advantageofthinking about drug effects along a continuum is that hard-to-classify drugs, suchasmori- cizineand amiodarone, can be positioned at appropriate points along the continuum instead of being arbitrarily assigned to a specificclass. The Vaughan-Williams classification system, thoughad- mittedly imperfect, helpstolocate drugs along the continuum,and therefore helpstoelucidate the electrophysiologic properties even of drugs that are difficult to formally classify. As ithappens, the Vaughan-Williamsscheme also allowsoneto make other clinically relevant generalizations aboutantiarrhythmic drugs. What emergedwas a new approach to the classification of antiarrhythmic drugs; the inventors imaginatively named the approach the Sicilian Gambit. The Vaughan-Williamsscheme is based onwhether drugs pro- duce block in oneormore of a few sites on the cell membrane, but the Sicilian Gambit takes into account a host of additional actions 50 Chapter 2 of antiarrhythmic drugs—the typeand degree of blockadeofchan- nels, antagonistic and agonistic effects on receptors, effects on the sodium–potassium pump, the time constants of binding to cellular sites, effects on second messengers, and the affinity for binding on the basisofwhether the cell is in an active or inactive state. Digoxin Relative potency of block: Low Moderate High A=Activated state blocker =Agonist =Agonist/Antagonist I = Inactivated state blocker Figure 2.

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Veterinarians and naturalists use etorphine darts to knock down wild elephants and grizzly bears buy generic cialis pills impotence at 40. Zoos utilize the drug on white rhinoceros purchase genuine cialis line valsartan causes erectile dysfunction, giraffes buy cialis mastercard erectile dysfunction natural cure, and other animals when medical necessity requires them to be unconscious. Human tests show that etorphine can relieve intense pain without causing unconsciousness. Tests using dihydroetorphine alone and in combination with acupuncture have found the drug to be safe and effective for easing labor pain in childbirth. Experiment- ers suspect that as well as being a more powerful pain reliever than morphine, dihydroetorphine may also be less likely to create dependence in a patient. Administered in a particular way, however, etorphine reliably pro- duces a “paradoxical” effect (opposite to an expected effect) of increasing athletic performance by stimulating physical activity while reducing pain. Many lovers of the sport disapprove of the practice not only for its illegality but because the horse is harmed. Perhaps the most notorious incident occurred in 158 Etorphine the late 1980s when Rocket Racer won the Perth Cup by eight lengths and continued running. The horse would not stop despite the jockey’s efforts; after nearly another lap around the track, the horse collapsed and died. Reportedly some human track competitors have used the same drug, accelerated their pace as a race progressed, and had difficulty stopping after crossing the finish line. In animal experiments dihydroetorphine interferes with the im- mune system, interference that may make infections more likely. Etorphine can send blood pressure up or down, reduce body temperature, and impair heartbeat and breathing. Impaired breathing is also an unwanted effect ob- served with dihydroetorphine, along with constipation, nausea, vomiting, diz- ziness, and drowsiness. Although etorphine is a standard veterinary medicine, knowledgeable users treat it with great respect and keep an antidote on hand because accidental injection can be fatal. The drug may be absorbed though the skin, and supplies of etorphine are generally dyed red so users can readily tell if they have touched it (such as a smear across a shirt or hand). The quantity needed to kill a person is so minute that its presence in a body can be difficult or even impossible to detect. Harmless chemicals added to a dose can make etorphine even harder to discover through laboratory tests. The drug has also attracted military attention as a possible chemical warfare agent. When humans in an experiment received etorphine they ex- perienced euphoria and described the drug as feeling like morphine. Research- ers who administered etorphine in that experiment concluded that the drug is likely to be abused. Other investigators reached the same conclusion about dihydroetorphine from the way rats re- sponded to it. Drug Enforcement Administration has ruled that dihy- droetorphine’s abuse potential is similar to heroin’s. The government of Hong Kong has noted dihydroetorphine’s lower price and less stringent control make it appealing to heroin addicts. Lawsuits against the tobacco industry unearthed documentation indicating one company considered the possibility that competitors might lace cigarettes with etorphine to add an addictive need that could not be satisfied by other brands, thereby coercing consumer loyalty to a particular product. A mice study found no dependence at all after dihydroetorphine had been administered for six days, but rat and mice research demonstrates that dihy- droetorphine eventually produces enough dependence to cause withdrawal symptoms. Investigators have noted that rats act as if dihydroetorphine is a satisfactory substitute for heroin. Etorphine can prevent withdrawal symp- toms in morphine addicts, an action demonstrating cross-tolerance between the two drugs, but an etorphine dose holds off withdrawal symptoms for a shorter time than morphine would. In rhesus monkey experiments etorphine and dihydroetorphine are both cross-tolerant with morphine. In those same experiments, when dihydroetorphine dosage was suddenly stopped, few withdrawal signs appeared. Withdrawal symptom research on mice indicates that dihydroetorphine may do more than substitute for morphine: A dihy- Etorphine 159 droetorphine dose may actually make morphine withdrawal symptoms go away, so further doses of either drug become unnecessary. Such a result would be inconsistent with what is known about opiate dependence, but dis- covery of new facts can change scientific understandings.