By A. Umul. Carleton College.

In some patients with re- The most important mechanism of bacterial resistance current UTIs purchase dapoxetine 30mg mastercard, most notably women of childbearing age buy generic dapoxetine 90 mg, to trimethoprim clinically is the production of plasmid- the long-term use of one tablet taken at night is an ef- encoded trimethoprim-resistant forms of dihydrofolate fective form of chemoprophylaxis buy 90mg dapoxetine mastercard. Food and Drug Administration Because trimethoprim and sulfamethoxazole have (FDA) for treating UTIs in both children and adults buy dapoxetine 60 mg on line. The combination ance to the combination is less than that observed when is also effective for covering the carrier state of the drugs are used individually. Resistance is an in- Salmonella typhi, the agent of typhoid fever, and other creasing problem in a number of bacteria, but is espe- Salmonella spp.. Trimethoprim is well absorbed from the GI tract, and Because trimethoprim accumulates in the prostate, peak blood levels are achieved in about 2 hours. Tissue TMP-SMX is used to treat prostatitis caused by sensi- levels often exceed those of plasma, and the urine con- tive organisms. Therapy can be prolonged (4–6 weeks) centration of trimethoprim may be 100 times that of the and repeat courses of therapy may be necessary. Trimethoprim readily enters the CSF if inflam- Trimethoprim alone, because of its lipid solubility, can mation is present. The half-life of the drug is approxi- be effectively used when patients exhibit an allergic re- mately 11 hours. Recently a second target, unique to the fluoro- TMP-SMX remains the antimicrobial therapy of quinolones, has been identified as topoisomerase type choice in both the treatment and prevention of infec- IV. In those with AIDS, treatment is belong to the general class of DNA enzymes called more prolonged and relapse is common. The effect of quinolones on these are at increased risk for untoward effects such as fever, DNA enzymes is initially bacteriostatic but becomes hepatitis, rash, and leukopenia. These drug targets may be primary or Adverse Effects and Drug Interactions secondary depending upon the organism; this observa- tion can affect the bacterial potential for the develop- Serious adverse effects are rare except in AIDS patients. Each generation and skin rashes are particularly common in patients with (first through fourth) has spectrum specificity and AIDS. Most of the adverse effects of this combination unique pharmacological properties, although there is are due to the sulfamethoxazole component. Tri- considerable overlap: First, nalidixic acid and cinoxacin; methoprim may increase the hematological toxicity of second, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, sulfamethoxazole. Increased levels of dapsone, warfarin, methotrexate, zidovudine, and sul- Antibacterial Spectrum and Resistance fonylureas may occur when given together with tri- The first-generation and oldest quinolones exhibit lim- methoprim; dosages of these drugs should be modified ited gram-negative activity. Although they are bactericidal agents, their such as the development of neural tube defects associ- use is restricted by resistance. The use of trimethoprim is The second-generation drugs demonstrate their most contraindicated in patients with blood dyscrasias, he- reliable activity against gram-negative organisms, includ- patic damage, and renal impairment. The antipseudomonal activity of ciprofloxacin, norfloxacin, Chemistry, Mechanism of Action, ofloxacin, and lomefloxacin is due to their piperazine and Classification moiety; resistance to these agents, however, is becoming All clinically approved quinolones in use in the United more prevalent. States contain a carboxylic acid moiety in the 3-position Significantly greater activity against gram-positive of the basic ring structure (the 4-quinolones). The fourth-generation quinolones also possess Therapeutic uses of the quinolones include urinary and activity against anaerobes. These has gained popular attention in providing coverage for drugs have shown efficacy in treating prostatitis and can Bacillus anthracis, a major bioterrorism agent. The primary mutation sites affected by organ- in the treatment of respiratory infections, although isms are topoisomerase IV and gyrA. Mutations at they may not be the drugs of choice; these infections in- these points influence the degree of resistance, with clude acute and chronic bacterial sinusitis. A second- lower levels of resistance associated with topoisomerase generation cephalosporin, such as cefuroxime, is usually IV and higher levels with gyrA. The sec- take of the drug and the appearance of an active efflux ond-generation quinolones usually have poor activity in system for transport of the drug out of the cell also con- treating community-acquired pneumonia (CAP) be- tribute to resistance.

Giving a larger dose or giving the dose more often ume but one that relates the blood concentration to the will not change the time needed to reach steady state amount of drug in the body buy 90 mg dapoxetine overnight delivery. Just as it takes approximately five half-lives for a Protein Binding drug to be essentially (97%) eliminated buy 90mg dapoxetine free shipping, it also requires five half-lives for a drug to reach steady state order 90mg dapoxetine mastercard. This is ex- Most drugs bind to plasma proteins such as albumin and emplified in the concentration–time profiles of Figure 1-acid glycoprotein (AGP) to some degree buy dapoxetine 60 mg with mastercard. The hypothetical drug in this example has a half-life comes clinically important as it is assumed that only un- of 8 hours and is dosed every 8 hours. The graph shows bound (free) drug is available for binding to receptors, that at about 40 hours (five half-lives), the maximum being metabolized by enzymes, and eliminated from the and minimum concentrations become consistent, indi- body. For example, phenytoin is approximately 90% bound to plasma proteins, leaving 10% of the concentration in the blood as free drug and available for pharmacologi- 1000 cal action and metabolism. If the presence of renal dis- ease or a drug interaction were to alter the degree of protein binding to only 80%, this change could have substantial clinical consequences. Even though the total t1/2 = 8hr percent bound changes relatively little, the net result is to double the amount of free drug. However, for most drugs, displacement from protein binding sites re- sults in only a transient increase in free drug concentra- tion, since the drug is rapidly redistributed into other body water compartments. Thus, interactions or changes 10 in protein binding in most cases have little clinical effect 0 despite these theoretical considerations. This nonlinearity often occurs be- cause the drug-metabolizing enzymes for the drug be- NONLINEAR PHARMACOKINETICS come saturated at typical blood concentrations, such that despite increases in dose, drug is still metabolized The underlying assumption in the discussion of these at the same rate and blood concentrations go up unex- concepts is that the drug of interest follows linear phar- pectedly. In this case, following Michaelis-Menten en- macokinetic principles; that is, the concentrations zyme kinetics, the maximum velocity (Vmax) has been achieved are proportional to the dose given. For exam- reached and the rate of drug metabolism remains con- ple, a doubling of the dose will produce a doubling of stant. For some drugs, however, this is not the case: an increase in dose may produce a con- centration much greater than expected. For example, in- creases in dosage of the antiepileptic agent phenytoin 60 above approximately 300 mg daily usually produce a 50 180 40 160 30 140 120 20 Phenytoin Therapeutic Range 100 10 80 60 0 40 Bolus dose + Continuous Infusion 20 Continuous Infusion Only 0 100 200 300 400 500 600 Phenytoin Dose (mg) 0 FIGURE 5. Within the either an intravenous bolus dose immediately followed by therapeutic range, a relatively small increase in dose results initiation of a continuous intravenous infusion or initiation of in a greater than proportional increase in concentration, a continuous intravenous infusion only. Frequently it is useful to consider the overall expo- (A) Theoretical dose sure of a person to a drug during the dosing inter- (B) Cmax val. Which of the following pharmacokinetic param- (C) Bioavailability eters defines the exposure of a person to a drug? The AUC (area under the curve) best describes (D) Half-life the overall exposure of a person to a given drug (E) Clearance over the course of the dosing interval. Organs such as the liver remove exogenous chemi- the concentration of drug integrated over the pe- cals, such as drugs, from the body. A (Cmax) is phenytoin, for which the difference between the not correct, as Cmax gives the maximum concentra- minimum effective concentration and the minimum tion achieved but does not reveal how long measur- toxic concentration is small, clinicians must calcu- able concentrations of the drug were present or late the rate at which a given individual removes how long until this concentration was achieved. The volume of fluid from which (Tmax) only refers to the time until the maximum drug can be completely removed per unit of time concentration is achieved, again not giving a refer- (rate of drug removal) is termed: ence to overall exposure over time. D (half-life) (A) Distribution simply describes how much time is required for the (B) Clearance concentration to decrease by one-half. Finally, clear- (C) Metabolism ance (E) is the volume of fluid (usually plasma) (D) Excretion from which drug can be removed per unit of time 3. Clearance is defined as the volume of fluid from hours), steady state will be reached shortly follow- which drug is completely removed per unit of time ing which DOSE (not which half-life)? Distribution is the theoreti- (C) 5th dose cal volume to which the drug distributes and me- (D) 8th dose tabolism and excretion are simply methods of (E) 12th dose clearing drug. Approximately five half-lives are required for a logical volume, helps a clinician to estimate drug drug to reach steady-state concentrations. Drugs distribute through- piroxicam has a half-life of 40 hours, it will require out the body to differing degrees depending on a approximately 200 hours before steady state is number of factors. Different drugs can have widely disparate vol- (D) In general, lipophilic drugs distribute to a umes of distribution, so B is incorrect. A clinician must be concerned with the amount of a distribution and can override plasma protein bind- drug dose that reaches the systemic circulation, ing, so C is incorrect. Finally, D is incorrect, since in since this will affect the plasma concentration and general the more lipophilic a drug is, the greater therapeutic effects observed.

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Due to a nearly complete pre- and arterial afterload generic 90 mg dapoxetine mastercard, cardiac work is systemic elimination order dapoxetine 60mg on-line, it is poorly suited decreased (p order dapoxetine 30 mg mastercard. Spas- livery (nitroglycerin patch) also avoids modic constriction of larger coronary presystemic elimination proven 60 mg dapoxetine. Organic nitrates are used through membranes, is more stable chiefly in angina pectoris (p. ISDN Continuous intake of higher doses with can also be applied sublingually; how- maintenance of steady plasma levels ever, it is mainly administered orally in leads to loss of efficacy, inasmuch as the order to achieve a prolonged effect. This “nitrate tolerance” can because of its higher polarity and slower be avoided if a daily “nitrate-free inter- rate of absorption. Af- of a throbbing headache, probably ter oral intake, it is slowly converted caused by dilation of cephalic vessels. Apparently, This effect also exhibits tolerance, even there is little likelihood of "nitrate tole- when daily “nitrate pauses” are kept. Excessive dosages give rise to hypoten- Sodium nitroprusside contains a sion, reflex tachycardia, and circulatory nitroso (-NO) group, but is not an ester. It is administered by infusion to tion in vascular smooth muscle tone is achieve controlled hypotension under presumably due to activation of guany- continuous close monitoring. Cyanide late cyclase and elevation of cyclic GMP ions liberated from nitroprusside can be levels. The causative agent is most likely inactivated with sodium thiosulfate nitric oxide (NO) generated from the or- (Na2S2O3) (p. NO is a physiological mes- senger molecule that endothelial cells release onto subjacent smooth muscle cells (“endothelium-derived relaxing factor,” EDRF). Organic nitrates would thus utilize a pre-existing pathway, hence their high efficacy. The genera- tion of NO within the smooth muscle cell depends on a supply of free sulfhy- dryl (-SH) groups; “nitrate-tolerance” Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Vasodilators 121 Preload Afterload O2-supply O2-demand Blood pressure Venous blood return Prevention of Peripheral to heart coronary artery resistance spasm Venous bed “Nitrate- Arterial bed tolerance” Route: Route: e. Vasodilators: Nitrates Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. It exerts inhibitory effects not only on During electrical excitation of the cell arterial smooth muscle, but also on heart membrane of heart or smooth muscle, muscle. In the heart, Ca2+ inward cur- different ionic currents are activated, rents are important in generating depo- including an inward Ca2+ current. The larization of sinoatrial node cells (im- term Ca2+ antagonist is applied to drugs pulse generation), in impulse propaga- that inhibit the influx of Ca2+ ions with- tion through the AV- junction (atrioven- out affecting inward Na+ or outward K+ tricular conduction), and in electrome- currents to a significant degree. Other chanical coupling in the ventricular car- labels are Ca-entry blocker or Ca-channel diomyocytes. Therapeutically used Ca2+ an- negative chrono-, dromo-, and inotropic tagonists can be divided into three effects. An effect ployed in the prophylaxis of angina pec- on cardiac function is practically absent toris attacks (p. AV-block and myocardial the dilatation of resistance vessels, insufficiency can occur. Indications for nifedipine include Diltiazem is a catamphiphilic ben- angina pectoris (p. Mibefradil tachycardia due to hypotension), head- shows relative selectivity for the latter ache, and pretibial edema. Ni- promised by numerous interactions modipine is given prophylactically after with other drugs due to inhibition of cy- subarachnoidal hemorrhage to prevent tochrome P450-dependent enzymes vasospasms due to depolarization by (CYP 1A2, 2D6 and, especially, 3A4). Verapamil con- tains a nitrogen atom bearing a positive charge at physiological pH and thus rep- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Vasodilators 123 Smooth muscle cell Afterload O2-demand Blood pressure Contraction Inhibition of Peripheral coronary spasm resistance Ca2+ Arterial blood vessel Vasodilation in arterial bed Na+ Ca2+-3 10 M Ca2+-7 K+ 10 M Selective inhibition of calcium influx Nifedipine Verapamil (dihydropyridine derivative) (cationic amphiphilic) Inhibition of cardiac functions Impulse Heart rate Sinus node generation Reflex tachy- Ca2+ cardia with nifedipine Impulse AV- AV-node conduction conduction Ventricular Electro- muscle mechanical Contractility coupling Heart muscle cell A. Vasodilators: calcium antagonists Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Indi- cations are hypertension and cardiac Angiotensin-converting enzyme (ACE) failure.

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However dapoxetine 90 mg overnight delivery, amphetamine and containing beverages buy dapoxetine 90 mg fast delivery, including coffee discount 90mg dapoxetine overnight delivery, tea discount 30 mg dapoxetine overnight delivery, cocoa, and methylphenidate are still considered among the drugs cola drinks. It is primarily for this reason that xanthines are other centrally acting adrenomimetics has been in the listed as CNS stimulants in this text. Although the amphetamines have a significant anorexic effect, Chemistry and Pharmacokinetics tolerance to this action develops within a few weeks. In addition, insomnia restricted their use during the latter Three xanthines are pharmacologically important: caf- part of the day. All three alka- opment of tolerance and potential for drug abuse have loids, which occur naturally in certain plants, are widely convinced much of the medical community that the use consumed in the form of beverages (infusions or decoc- of amphetamines in weight control is inappropriate. Coffee primarily con- Fenfluramine (Pondimin) and phentermine (Adipex- tains caffeine (about 100–150 mg per average cup); tea P, Fastin) are anorexigenic drugs that produce depres- contains caffeine (30–40 mg per cup) and theophylline; sion of the CNS and at one time were used (Fen-phen) and cocoa contains caffeine (15–18 mg per cup) and in the treatment of obesity. The CNS stimulation associated with these beverages is predomi- Adverse Effects nantly due to the caffeine. The xanthines are readily absorbed by the oral and The acute effects of psychomotor stimulant overdoses rectal routes. Although these agents can be adminis- are related to their CNS stimulant properties and may tered by injection (aminophylline is a soluble salt of include euphoria, dizziness, tremor, irritability, and in- theophylline), intravascular administration is indicated somnia. At higher doses, convulsions and coma may en- only in status asthmaticus and apnea in premature in- sue. Intramuscular injection generally produces con- headache, palpitation, cardiac arrhythmias, anginal siderable pain at the injection site. Dextro- The compounds are extensively metabolized, prima- amphetamine produces somewhat less cardiac stimula- rily to uric acid derivatives. These agents produce addiction, including psycholog- Mechanism of Action ical dependence, tolerance, and physical dependence. The mechanism of action of methylxanthine-induced Psychic dependence also has been seen following high stimulation of the CNS has been the subject of much in- doses of methylphenidate. The abstinence syndrome seen vestigation, and at least two other possible mechanisms after abrupt discontinuation of amphetamines is neither of action of the methylxanthines have been suggested. With the to act as antagonists of the naturally occurring com- amphetamines, the abstinence syndrome consists prima- pound adenosine, a substance that can inhibit both neu- rily of prolonged sleep, fatigue, and extreme hunger (hy- ronal activity and behavior through direct postsynaptic perphagia). These symptoms may be accompanied by action on neurons and through indirect action involving profound and long-lasting depression. Thus, as an equilibrium-competitive antagonist of adenosine, the methylxanthines may pro- XANTHINES duce excitation either by direct blockade of inhibitory The compounds known as xanthines, methylxanthines, effects of adenosine at the neuron or by an antagonism or xanthine derivatives constitute a particularly inter- of the presynaptic inhibitory effect of adenosine on the esting class of drugs. Caffeine can compete for binding at the Xanthines (usually caffeine) are frequently combined benzodiazepine site and would therefore be expected to with aspirin in the treatment of headaches. Thus, caffeine may act tion with an ergot derivative, methylxanthines have functionally like the analeptic stimulants that limit chlo- been used to treat migraine. Central Nervous System Xanthines, primarily as the intramuscularly adminis- Adverse Effects tered combination of caffeine and sodium benzoate, have been used in the treatment of CNS depressant Toxicity associated with the methylxanthines usually overdosage. Black coffee has been used to physiologi- takes the form of nervousness, insomnia, and in severe cally antagonize alcohol intoxication, although many cases, delirium. Cardiovascular stimulation is seen as physicians believe that this ineffective therapy simply tachycardia and extrasystoles. Many over-the-counter preparations are aimed at The intravenous administration of aminophylline relieving fatigue through CNS stimulation. Such com- (or theophylline) may present some problems if the pounds are often referred to as wake-up tablets, but drug is given too rapidly. In such cases, severe headache, these methylxanthine-containing products do little to hypotension, and palpitation accompany drug adminis- offset physical fatigue, so they place individuals using tration. Diuresis Abuse of Xanthines All the xanthines, but especially theophylline, are capa- ble of producing some degree of diuresis in humans. The use of some xanthine-containing beverages is cus- This specific action of the methylxanthines is discussed tomary in most cultures, and moderate use of such bev- in greater detail in Chapter 21.

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