By Z. Hector. Webster University Orlando. 2018.
As drug nonspeciﬁc; that is order silvitra 120 mg with visa erectile dysfunction over the counter, many drugs may interact with the dosage increases silvitra 120 mg without prescription erectile dysfunction pump demonstration, eventually the binding capacity of the same binding site. A drug with a higher afﬁnity may dis- protein becomes saturated and any additional drug will place a drug with weaker afﬁnity. However, in practice, changes in protein bind- culation, thereby slowing the rate of transfer across the ing result in clinically signiﬁcant effects for only a lim- capillary. Thus, binding poalbuminemia, uremia, hyperbilirubinemia) have been does not prevent the drug from reaching its site of ac- associated with changes in plasma protein binding of tion but only retards the rate at which this occurs. For example, in uremic patients the plasma pro- Extensive plasma protein binding may prolong drug tein binding of certain acidic drugs (e. Drugs that are Lipoproteins highly bound to plasma proteins may distribute less widely because they remain trapped in the peripheral vas- Drugs that bind to lipoproteins do so by dissolving in culature, since the plasma proteins themselves cannot tra- the lipid portion of the lipoprotein core. The binding 30 I GENERAL PRINCIPLES OF PHARMACOLOGY capacity of individual lipoproteins generally depends (e. The lung receives the entire cardiac out- the drug ﬁrst binding to a number of sites on the protein put; therefore, drug distribution into it is very moiety and then dissolving in the lipid phase. However, some nonbasic psychotherapeutic drugs chlorpromazine, imipramine, amines, such as the herbicide paraquat, also spiroperidol, and nortriptyline, is becoming apparent. Although bone is a relatively inert tissue, certain physiological and pathological conditions, such it can accumulate such substances as tetracy- as injury, stress, surgery, trauma, rheumatoid arthritis, clines, lead, strontium, and the antitumor agent and celiac disease. These substances may accumulate in bone by absorption onto the bone crystal sur- face and eventually be incorporated into the crystal lattice. Tetracycline deposition during SELECTIVE ACCUMULATION OF DRUGS odontogenesis may lead to a permanent yel- Drugs will not always be uniformly distributed to and low-brown discoloration of teeth, dysplasia, retained by body tissues. Lead can substi- drugs will be either considerably higher or considerably tute for calcium in the bone crystal lattice, re- lower in particular tissues than could be predicted on sulting in bone brittleness. This obser- reservoir for the slow release of toxic sub- vation is demonstrated in the following examples: stances, such as lead and cisplatin. Since the kidneys receive 20 to 25% of the cardiac output, they will be exposed to a rel- PHYSIOLOGICAL BARRIERS TO DRUG atively large amount of any systemically admin- DISTRIBUTION istered drug. The kidney also contains a protein, metallothionein, that has a high afﬁnity for Blood-Brain Barrier metals. Several drugs have an afﬁnity for the reti- cells is much less permeable to water-soluble drugs than nal pigment melanin and thus may accumulate is the membrane between plasma and other tissues. Chlorpromazine and other phe- Thus, the transfer of drugs into the brain is regulated by nothiazines bind to melanin and accumulate in the blood-brain barrier. To gain access to the brain from the uveal tract, where they may cause retino- the capillary circulation, drugs must pass through cells toxicity. Only drugs that have a high can be approximately 100 times that found in lipid–water partition coefﬁcient can penetrate the the liver. Drugs with extremely high lipid–water Drugs that are partially ionized and only moderately partition coefﬁcients have a tendency to accu- lipid soluble will penetrate at considerably slower rates. However, since blood ﬂow Lipid-insoluble or highly ionized drugs will fail to enter to adipose tissue is low (about 3 mL/100 the brain in signiﬁcant amounts. In addition, because only the unbound form of tion or in prolonged activity when only low a drug is available for diffusion, extensive plasma pro- levels of the drug are needed to produce ther- tein binding also can have dramatic effects on the ex- apeutic effects. Should body fat be seriously re- or encephalitis, may increase the permeability of the duced, as during starvation, stored compounds blood-brain barrier, permitting the passage of ionized 3 Drug Absorption and Distribution 31 lipid-insoluble compounds (e. The ﬂow of cerebrospinal ﬂuid is essentially unidirec- In general, substances that are lipid soluble cross the tional; that is, it ﬂows from its site of formation in the placenta with relative ease in accordance with their choroid plexus through the ventricles to its site of exit at lipid–water partition coefﬁcient and degree of ioniza- the arachnoid villi. Highly polar or ionized drugs do not cross the pla- brain tissue or be returned to the venous circulation in centa readily. However, most drugs used in labor and the bulk ﬂow of cerebrospinal ﬂuid carried through the delivery are not highly ionized and will cross. Some drugs, such as penicillin, will not generally weak bases with pKa values of about 8 and leave the cerebrospinal ﬂuid compartment by bulk ﬂow tend to be more ionized in the fetal bloodstream, since but will be actively transported by the choroid plexus out the pH of fetal blood is around 7. As in the gut, the Pgp transporter sys- Pgp, multidrug resistance–associated protein (MRP), tem is the primary active transporter in the blood-brain and breast cancer resistance protein (BCRP). This ATP-dependent trans- transport proteins are located in many tissues but also porter system picks up substrates that have crossed the appear to be expressed in the placenta. Though the sub- capillary endothelial cells and transports them back to strate speciﬁcities of these proteins have not been com- the systemic circulation, limiting their penetration into pletely described, they appear to function as efﬂux the CNS. Thus, not only are the physicochemical prop- transporters, moving endogenous and exogenous chem- erties of the drug a determinant for penetration into the icals from the placental cells back to the systemic circu- CNS but penetration also depends on whether the drug lation.
Regular use of high-alcohol rinses can ag- tition free of supragingival and subgingival plaque is ex- gravate existing oral lesions and desiccate mucous tremely difﬁcult to accomplish and maintain buy silvitra 120 mg on line erectile dysfunction treatment germany. In addition to Listerine order 120 mg silvitra with mastercard erectile dysfunction treatment hong kong, a huge number of annual basis, Americans spend more than $750 million American Dental Society (ADA) approved generic on oral rinsing agents, although few effective plaque-in- equivalents available over the counter. The goal of future product development is not so Fluorides much an improvement in the antiplaque performance Fluorides are widely used in caries prevention, for which of the existing effective compounds but rather lessening they have been highly effective. Systemic administration of their side effects and development of better delivery of ﬂuorides for caries prevention is available via drink- systems. Products that combine various known com- 42 Drugs for the Control of Supragingival Plaque 505 pounds with well-established plaque-inhibiting proper- vention of supragingival plaque will depend on prod- ties are under investigation. The other four compounds are substrate in the oral cavity is not cationic and do not bind strongly to tissues. Triclosan (A) is active against a broad range of (B) Absorption oral gram-positive and gram-negative bacteria. Yellow or brownish extrinsic stain of teeth is a fre- bacteria, but Streptococcus mutans and Actinomyces quently observed side effect of viscosus, two bacteria particularly associated with (A) Fluoride dental lesions, are especially susceptible to its ac- (B) Triclosan tion. Stannous ﬂuoride (D) is widely used in caries (C) Essential oils prevention, and many studies have proven its effec- (D) Chlorhexidine tiveness. The LEAST effective chemical agent for reduction shown to decrease supragingival plaque in combina- of dental plaque is tion with the polymer in a commercial preparation. Proceedings of the 2nd involved in drug elimination, while absorption (B) European Workshop on Periodontology. Rinsing, irrigation and sustained local scribes the ability of a drug to enter a variety of body delivery. In most instances, dental plaque can cause ery- Administration was evaluating the results of a new thema and gingival bleeding, but the gingival re- drug for the treatment of periodontal disease. Her sponse can also be exacerbated by a variety of review of the phase III clinical data caused her to systemic conditions, including diabetes mellitus, visit her dentist, since she was concerned that her leukemia, malnutrition, puberty and pregnancy. For exam- revealed swollen and tender gingiva that were ple, the age of the patient, her appearance, and accompanied by erythema and bleeding upon mild questions about her diet should be enough to provocation. Her dental radiographs revealed no rule in or out issues concerning puberty and mal- abnormalities, and her physician found her to be nutrition. She reports be ruled out, an additional physical examination taking no medications and denies allergies to any by a physician may be necessary. She is concerned about her health to be requested could include oral glucose toler- because her gingiva will bleed when she eats ﬁbrous ance test for diabetes mellitus, human chorionic foods (e. What do you think is the most likely cause of her tative and quantitative evaluation of bone mar- periodontal disease? Should an oral chemotherapeutic agent be pre- using over-the-counter toothpastes with triclosan scribed for her periodontal disease? If the patient one would you prescribe and what would be the is pregnant, a thorough review of oral hygiene beneﬁt and disadvantage of using this agent for combined with over-the-counter toothpaste with this patient? If persistent in- ﬂammation and gingival enlargement continue, the use of a prescription antiplaque rinse, such as chlorhexidine, would be warranted. Therapy of Human Immunodeﬁciency Sulfonamides, Trimethoprim, Nitrofurans, Virus 584 Quinolones, Methenamine 515 Knox Van Dyke and Karen Woodfork Marcia A. Lazo and Jennifer Rubin Grandis Introduction to Chemotherapy 4343 Steven M. Belknap Paul Ehrlich introduced the term chemotherapy toxic substances that kill or suppress the growth of com- in 1907 to describe his important early studies of peting microorganisms or facilitate infection of a host. Trypanosoma brucei, the tsetse ﬂy–borne parasite that Plants make a vast array of toxins for their self-defense. The Exploitation of the selective toxicity of chemicals is an term chemotherapy, initially referring to antiparasitic ancient and widely employed technique. Ehrlich had previously developed selective bacterial effect of a substance secreted by Penicillium chemical stains for the microscopic examination of notatum mold.
As seen in the BF- and FRF-centered average tuning curves proven silvitra 120 mg erectile dysfunction causes symptoms and treatment, RSUs (red curve) and trigeminal neurons (green) demonstrated more reﬁned tuning than FSUs (blue) and MUA (purple) for both averaging approaches buy cheap silvitra 120 mg on line impotence juicing. A consistent difference was observed in the speciﬁcity of tuning between recorded cell classes. The excitatory neuron classes in the periphery and SI, trigem- inal neurons and RSUs, showed signiﬁcantly more precise tuning than the FSUs (Figures 2. The greater precision observed in the frequency tuning of RSU responses parallels the tuning precision observed for other features in SI, as RSUs also tend to have more precise spatial tuning and more precise direction-of- deﬂection representations. Complex Stimuli We also recorded the neural response in a subset of neurons evoked by natural and complex stimuli. As the speed of sandpaper motion was increased, the relative frequency of vibration of the vibrissa tip was correspondingly increased. Larger vibrissa oscillations were observed when the speed of the wheel combined with the prominent spatial frequencies of the sandpaper to drive the vibrissa at its resonance. In accordance, a greater mean ﬁring rate was also observed in this recording when the vibrissa was driven at its resonance. These stimulus-generated velocities of vibrissa surface interaction are within the physiological range21,56 suggesting that increases in mean ﬁring rate should be observed in the awake behaving animal as they explore textured surfaces. In further experiments in the periphery and SI, we created white noise stimuli that were the sum of all sinusoids from 0–600 Hz, where each sinusoid was calibrated to 80 µm amplitude and randomly phase shifted. These stimuli were then notch ﬁltered by selectively removing frequencies that would have driven vibrissa resonance while compensating for the total power in the stimulus across frequencies. When complex stimuli were applied without notching, a robust vibrissa resonance was observed and correspondingly, a signiﬁcant increase in the mean ﬁring rate (Figure 2. When the majority of frequencies ampliﬁed by vibrissa resonance were removed, resonance was not observed and the mean ﬁring rate was also signiﬁcantly lower. These examples demonstrate that the neural correlates of vibrissa resonance are observed even when more natural and/or complex stimuli are presented to the vibrissa. SOMATOTOPIC FREQUENCY MAPPING AND ISOFREQUENCY COLUMNS A potentially important consequence of the discovery of vibrissa resonance was the simultaneous discovery of a novel frequency map laid across the somatotopic map of the face. Multi-unit activity was recorded in the trigeminal ganglion while a stimulus wheel covered in 80-grit sandpaper was rolled against the primary vibrissa (see Figure 2. As the wheel velocity increased, so did the vibrissa oscillation velocity (blue line). Vibrissa resonance ampliﬁcation can be observed in the spike in vibrissa velocity (P(f)*f, top) at a wheel speed of 800 mm/s. Neural activity also showed a spike in mean ﬁring rate at this velocity (green line). Neural activity also demonstrated a thresholded sensitivity to the increasing velocity of vibrissa oscillation at higher frequencies (≥ a wheel speed of 2000 mm/sec; see also Figure 2. Power spectra showing increased velocity of vibrissa motion or increased amplitude of neural activity (bottom) as a function of oscillation frequency and wheel speed. In the top panel, the peak in velocity signal at ~350 Hz (global increase in power) reﬂects the increased velocity of vibrissa motion generated when the wheel speed drove the pre- dominant spatial frequency present in the texture (shown in the diagonal bands) at the vibrissa resonance (blue box). The increased mean ﬁring rate in the associated neural response is indicated by the vertical band of increased activity observed at a wheel speed of 800 mm/s in the bottom panel. Note also that a peak is present in MUA power spectrum at the vibrissa resonance (~350 Hz), indicating ﬁne temporal ﬁdelity of spiking activity in response to a complex stimulus presentation (see also Figures 2. White noise stimuli constructed as the sum of phase-shifted sinusoids from 0–600 Hz were presented through a piezoelectric stimulator to the vibrissa. A notched stimulus was also created in which the fundamental resonance and surrounding frequencies (400–500 Hz) were removed from the stimulus and the power adjusted across remaining frequencies. Vibrissa oscillations showed a resonance ampliﬁcation at ~450 Hz when white noise stimuli were applied (green line) that is not present when notched stimuli were applied (blue line). These complex stimuli were presented while recording from a trigeminal ganglion single unit. As predicted by the differential increase in vibrissa motion, greater mean ﬁring rate was evoked by the non-notched (green bar) than the notched stimulus (blue bar) (N = 37 trials, mean ± SE). As predicted by the consistent agreement between neural tuning and vibrissa tuning (Figure 2. Because vibrissae in the same arc possess similar lengths, they also possess similar resonance tuning, creating a band of vibrissae with similar frequency encoding properties and a systematic network of putative cortical isofrequency columns. Vibrissae along an arc may, in several perceptual contexts, encode substantially different kinds of inputs.
In deep and in forced inspiration additional muscles attached to the chest wall are called into play (e trusted silvitra 120mg popular erectile dysfunction drugs. Similarly discount silvitra 120 mg with mastercard do herbal erectile dysfunction pills work, in deep expiration, forced contraction of the abdomi- nal muscles aids the normal expulsive factors described above. Each pleura consists of two layers: a visceral layer intimately related to the surface of the lung, and a parietal layer lining the inner aspect of the chest wall, the upper surface of the diaphragm and the sides of the pericardium and medi- astinum. The surface markings of the pleura and lungs have already been described in the section on surface anatomy. Notice that the lungs do not occupy all the available space in the pleural cavity even in forced inspiration. Clinical features 1Normally the two pleural layers are in close apposition and the space between them is only a potential one. It may, however, ﬁll with air (pneu- mothorax), blood (haemothorax) or pus (empyema). The lower respiratory tract 19 2Fluid can be drained from the pleural cavity by inserting a wide-bore needle through an intercostal space (usually the 7th posteriorly). The needle is passed along the superior border of the lower rib, thus avoiding the intercostal nerves and vessels (Fig. An incision is made through skin and fat and blunt dis- section carried out over the upper border of the 6th rib. The pleura is opened, a ﬁnger inserted to clear any adhesions and ensure the safety of the adjacent diaphragm before inserting a tube into the pleural space and con- necting it to an under-water drain. It commences at the lower border of the cricoid cartilage (C6) and terminates by bifurcating at the level of the sternal angle of Louis (T4/5) to form the right and left main bronchi. Thoracic In the superior mediastinum its relations are: •anteriorly—commencement of the brachiocephalic (innominate) artery 20 The Thorax Fig. The lower respiratory tract 21 Pretracheal fascia Anterior jugular (containing thyroid, vein trachea, oesophagus and recurrent nerve) Investing fascia Sternocleidomastoid Sternohyoid Sternothyroid Omohyoid External jugular vein Fig. Structure The patency of the trachea is maintained by a series of 15–20 U-shaped car- tilages. Posteriorly, where the cartilage is deﬁcient, the trachea is ﬂattened and its wall completed by ﬁbrous tissue and a sheet of smooth muscle (the trachealis). Clinical features Radiology Since it contains air, the trachea is more radio-translucent than the neigh- bouring structures and is seen in posteroanterior and lateral radiographs as a dark area passing downwards, backwards and slightly to the right. In the elderly, calciﬁcation of the tracheal rings may be a source of radiological confusion. Displacement The trachea may be compressed or displaced by pathological enlargement 22 The Thorax 2nd costal cartilage Internal thoracic artery and veins Thymus Superior vena cava Right phrenic nerve Left phrenic nerve Azygos vein Right vagus Left vagus nerve nerve Trachea Left recurrent Oesophagus laryngeal nerve Aortic arch T4 Thoracic duct Fig. Tracheostomy Tracheostomy may be required for laryngeal obstruction (diphtheria, tumours, inhaled foreign bodies), for the evacuation of excessive secretions (severe postoperative chest infection in a patient who is too weak to cough adequately), and for long-continued artiﬁcial respiration (poliomyelitis, severe chest injuries). It is important to note that respiration is further assisted by considerable reduction of the dead-space air. Avertical incision is made downwards from the cricoid cartilage, passing between the anterior jugular veins. Alternatively, a more cosmetic transverse skin crease incision, placed halfway between the cricoid and suprasternal notch, is employed. Ahook is thrust under the lower border of the cricoid to steady the trachea and pull it forward. The pretracheal fascia is split longitudinally, the isthmus of the thyroid either pushed upwards or divided between clamps and the cartilage of the trachea clearly exposed. The lower respiratory tract 23 In children the neck is relatively short and the left brachiocephalic vein may come up above the suprasternal notch so that dissection is rather more difﬁcult and dangerous. In contrast, the trachea may be ossiﬁed in the elderly and small bone shears required to open into it. If this is not done, major vessels are in jeopardy and it is possible, although the student may not credit it, to miss the trachea entirely. Before joining the lung it gives off its upper lobe branch, and then passes below the pulmonary artery to enter the hilum of the lung. It has two important relations: the azygos vein, which arches over it from behind to reach the superior vena cava, and the pulmonary artery which lies ﬁrst below and then anterior to it. The left main bronchus is nearly 2 in (5cm) long and passes downwards and outwards below the arch of the aorta, in front of the oesophagus and descending aorta.
Any growth of bacteria on an in-and- out catheterized or suprapubic specimen is considered to represent a true infection discount silvitra 120 mg line johns hopkins erectile dysfunction treatment. The lab as- sumes that more than three organisms growing on a culture represents a contaminant and the specimen collection should be repeated silvitra 120 mg sale impotence treatment drugs. The exception occurs in patients with a chronic in- dwelling Foley catheter that may be colonized with multiple bacterial or fungal organisms; the lab should be told to “culture all organisms” in such cases. VIRAL CULTURES AND SEROLOGY The laboratory provides the proper collection container for the specific virus. Common pathogenic viruses cultured include herpes simplex (from genital vesicles, throat), CMV (from urine or throat), varicella-zoster (from skin vesicles in children with chickenpox and 7 adults with shingles), and enterovirus (rectal swab, throat). For serologic testing, obtain an acute specimen (titer) as early as possible in the course of the illness, and take a convalescent specimen (titer) 2–4 wk later. A fourfold or greater rise in the convalescent titer compared with the acute titer indicates an active infection (see Chapter 4 for selected viral antibody titers). With the development of PCR techniques, biopsies performed on older lesions may yield useful information when cultures might be negative. SCOTCH TAPE TEST Also known as a “pinworm preparation,” this method is used to identify infestation with En- terobius vermicularis. The slide is applied to the perianal skin in four quadrants and examined under the microscope for pinworm eggs. The best sample is collected either in the early morning prior to bathing or several hours after retiring. MOLECULAR MICROBIOLOGY Molecular techniques can now identify many bacterial and viral organisms without cultur- ing. The following includes some microbes commonly identified from clinical specimens (ie, swab, serum, tissue). Common Microorganisms Identifiable by PCR/DNA Probe • Chlamydia trachomatis • Borrelia burgdorferi (Lyme disease) • HIV • Mycoplasma pneumoniae • Mycobacterium tuberculosis • Neisseria gonorrhoeae • Hepatitis B • HPV • Many others under development 7 Clinical Microbiology 133 SUSCEPTIBILITY TESTING To more effectively treat a specific infection by choosing the right antibiotic, many labs rou- tinely provide the MIC or MBC. MIC (Minimum Inhibitory Concentration) This is the lowest concentration of antibiotic that prevents an in vitro growth of bacteria. The organism is tested against a battery of antimicrobials in concentrations normally achieved in vivo and reported as Susceptible (S): The organism is inhibited by the agent in the usual dose and route, and the drug should be effective. Intermediate (I): Sometimes also reported as “indeterminate,” this implies that high 7 doses of the drug, such as those achieved with parenteral therapy (IM, IV), most likely in- hibit the organism. Resistant (R): The organism is resistant to the usual levels achieved by the drug. MBC (Minimum Bactericidal Concentration) Similar to the MIC, but indicates the lowest antibiotic concentration that will kill 99. The MBC results in killing the organisms, and the MIC prevents growth but may not kill the organism. Schlichter Test (Serum Bacteriocidal Level) Used to determine the antibacterial level of the serum or CSF of patients who are receiving antibiotic therapy. The test is usu- ally coordinated by the departments of infectious disease and microbiology. One set of blood or CSF cultures must be negative for the infecting organism before the test is per- formed. Optimal killing of the or- ganism occurs at dilutions of blood (and CSF) ranging anywhere from a trough of 1:4 to a peak of 1:8. Some data suggest higher titers (1:32) are needed to treat bacterial endocarditis. For the test to be performed, the organisms responsi- ble for the infection must be isolated from a patient specimen. DIFFERENTIAL DIAGNOSIS OF COMMON INFECTIONS AND EMPIRIC THERAPY The pathogens causing common infectious diseases are outlined in Table 7–2 along with some empiric therapeutic recommendations. The antimicrobial drug of choice for the treat- ment of infection is usually the most active drug against the pathogenic organism or the least toxic alternative among several effective agents.
Space Cadets Corner featuring:
Ares: US space program - talk by Hall and Jenkins 9/06
Asteroid Dreams - Astra's story about asteroid exploration