By M. Amul. Vassar College. 2018.
A4) generic voveran sr 100 mg amex, the smaller vature order 100mg voveran sr with visa,whereasOLDischaracterizedbyphysi- one (∆P2 high) would normally become even cal narrowing of the airways order voveran sr 100 mg fast delivery, as in asthma purchase voveran sr 100mg fast delivery, smaller while the larger one (∆P1 low) be- bronchitis, emphysema, and vocal cord paraly- comes larger due to pressure equalization. Surfactantisamixtureof Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Surface tension (soap bubble model) r1> r2 ∆P1< ∆P2 ∆P r r1 ∆P r2 ∆P r ∆P1 ∆P2 r 1 2 3 4 B. Maximum breathing capacity (MBC) Maximum respiratory depth and rate +2 Normal +1 Abnormal 0 –1 10s Spirometer Paper feed C. Forced expired volume in first second (FEV1) Maximum expiratory rate +2 +1 Abnormal 0 Normal –1 1s Paper feed 1 Measurement 1. Multiply- O2 diffuses about 1–2µm from alveolus to ing these volumes by the respiratory rate (f in bloodstream (diffusion distance). If,atagiventotalventi- long enough for the blood to equilibrate with lation (VE = VT! When f is doubled and VE T drops to one- blood enters the arterialized blood through. This extra-alveolar shunt as well as ventilation–per- Alveolar gas exchange can therefore decrease fusion inequality (! O2 consumption (VO2) is calculated as the The small pressure difference of about differencebetween. VO2 and VCO2 increase about tenfold cardiacoutput),thecontacttimefallstoathird during strenuous physical work (. Cases B2 and B3 lead to an increase in (100mmHg) and that of CO2 (PACO2) is about functional dead space (! The mean partial pres- B4 lead to inadequate arterialization of the sures in the “venous” blood of the pulmonary blood (alveolar shunt, i. Impairment of alveolar gas exchange Expiration CO2 Inspiration O2 1 Bronchial system Normal alveolar ventilation and perfusion Extra-alveolar shunt From pulmonary artery 4 Non-ventilated alveolus 2 Absent blood flow Alveolar shunt Functional dead space To 3 pulmonary veins Diffusion barrier 121 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. In this case, the PAO2 will fluctuate between Ventilation–Perfusion Ratio mixed venous PVO2 and PIO2 of (humidified). B, green line); PAO2 (PACO2) is flowtothelungs,isequaltothecardiacoutput therefore 17. These changes P decreases to about 12mmHg (Pprecap) in the are less pronounced during physical exercise. These values VA/Q imbalance decreases the efficiency of apply to the areas of the lung located at the the lungs for gas exchange. Due to the additive effect of hydrostatic pres- value, the relatively small Q fraction of zone 1. Near the olar–arterial O2 difference (AaDO2) exists (nor- apex of the lung, Pprecap decreases in vessels above mally about 1. Ppostcap), while the sharply, receptors in the alveoli emit local sig- area near the base of the lung (! A, zone 3) is con- nals that trigger constriction of the supplying tinuouslysuppliedwithblood(P. This throttles shunts in poorly Q per unit of lung volume therefore decreases from the apex of the lung to the base (! Life- decreases from the apex to the base of the lung threatening lung failure can quickly develop if (! The mean VA/Q for the entire fusion barrier, or surfactant disorder exists lung is 0. V /Q can A Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Regional blood flow in the lung (upright chest position) Alveolus Zone 1 PA> Pprecap> Ppostcap Pulmonary Pulmonary artery vein Zone 2 Pprecap> PA> Ppostcap Lung Zone 3 Pprecap> Ppostcap> PA Pprecap PA Ppostcap Perfusion Q · · B. Effect of ventilation-perfusion ratio (VA/Q) ventilation of lung on partial pressures in lung Pressures in kPa Ambient air: PO2= 20, PCO2= 0 VA/Q 0 3 Apex VA= 0 VA VA 2 VA Q PO2 = 5. Deoxygenated hemoglobin (Hb) can bycellsofthebodyundergoesphysicaldissolu- take up more H+ ions than oxygenated tion and diffuses into adjacent blood capillar- hemoglobin (Oxy-Hb) because Hb is a weaker ies. This promotes CO2 uptake in the dissolved,whiletherestischemicallyboundin peripheral circulation (Haldane effect) because form of HCO3– and carbamate residues of of the simultaneous liberation of O2 from ery- hemoglobin (!
Final- cles voveran sr 100 mg otc, however order voveran sr 100 mg line, penetrate the membrane ly voveran sr 100 mg with mastercard, signalling substances can originate easily buy cheap voveran sr 100mg line. The effect of a drug frequently re- sults from interference with cellular function. Receptors for the recognition of endogenous transmitters are obvious sites of drug action (receptor agonists and antagonists, p. Drugs may also directly interfere with intracellular metabolic processes, for instance by inhibiting (phosphodiesterase inhibitors, p. In contrast to drugs acting from the outside on cell membrane constituents, Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Cellular Sites of Action 21 1 Neural control D Nerve Transmitter Receptor Ion channel Cellular Hormonal transport control systems for Hormones controlled transfer of D substrates Hormone D receptors Transport molecule Enzyme D Direct action D = Drug on metabolism 2 Choline 3 D D Phosphoric acid Phospholipid matrix Glycerol Protein Fatty acid Effect Intracellular site of action A. Sites at which drugs act to modify cell function Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. These boundaries are formed by vided by the amount in the gut available the skin and mucous membranes. When absorption takes place in the In the respiratory tract, cilia-bear- gut (enteral absorption), the intestinal ing epithelial cells are also joined on the epithelium is the barrier. This single- luminal side by zonulae occludentes, so layered epithelium is made up of ente- that the bronchial space and the inter- rocytes and mucus-producing goblet stitium are separated by a continuous cells. A zonula occludens or nized, multilayered squamous epitheli- tight junction is a region in which the um of the oral mucosa. Here, the cells phospholipid membranes of two cells establish punctate contacts with each establish close contact and become other in the form of desmosomes (not joined via integral membrane proteins shown); however, these do not seal the (semicircular inset, left center). Instead, the cells gion of fusion surrounds each cell like a have the property of sequestering phos- ring, so that neighboring cells are weld- pholipid-containing membrane frag- ed together in a continuous belt. In this ments that assemble into layers within manner, an unbroken phospholipid the extracellular space (semicircular in- layer is formed (yellow area in the sche- set, center right). In this manner, a con- matic drawing, bottom left) and acts as tinuous phospholipid barrier arises also a continuous barrier between the two inside squamous epithelia, although at spaces separated by the cell layer – in an extracellular location, unlike that of the case of the gut, the intestinal lumen intestinal epithelia. A similar barrier (dark blue) and the interstitial space principle operates in the multilayered (light blue). The efficiency with which keratinized squamous epithelium of the such a barrier restricts exchange of sub- outer skin. The presence of a continu- stances can be increased by arranging ous phospholipid layer means that these occluding junctions in multiple squamous epithelia will permit passage arrays, as for instance in the endotheli- of lipophilic drugs only, i. The con- pable of diffusing through phospholipid necting proteins (connexins) further- membranes, with the epithelial thick- more serve to restrict mixing of other ness determining the extent and speed functional membrane proteins (ion of absorption. In addition, cutaneous ab- pumps, ion channels) that occupy spe- sorption is impeded by the keratin cific areas of the cell membrane. Eligible drugs are those whose physicochemical properties al- low permeation through the lipophilic membrane interior (yellow) or that are subject to a special carrier transport mechanism. Absorption of such drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Distribution in the Body 23 Ciliated epithelium Nonkeratinized squamous epithelium Epithelium with Keratinized squamous brush border epithelium A. External barriers of the body Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Penetrability of mac- Drugs are transported in the blood to romolecules is determined by molecu- different tissues of the body. Fenestrat- reach their sites of action, they must ed endothelia are found in the capillar- leave the bloodstream. The capillary wall forms the blood-brain barrier, drugs must diffuse blood-tissue barrier.
Binding studies with high-afﬁnity receptor antago- nists revealed four subtypes of muscarinic receptors that can be distinguished on the basis of (1) the rank or- DIRECT-ACTING der of potency of speciﬁc antagonists in functional ex- PARASYMPATHOMIMETIC DRUGS periments and (2) the afﬁnity of these antagonists for muscarinic receptors in the same tissues buy voveran sr 100mg low cost. More recently order voveran sr 100 mg overnight delivery, Acetylcholine molecular studies have revealed ﬁve genetically distinct receptor subtypes cheap voveran sr 100 mg fast delivery, named M1 through M5 cheap voveran sr 100 mg free shipping, the ﬁrst four Acetylcholine is an ester of choline and acetic acid, the of which correspond to functionally deﬁned receptors. The choline moiety of ACh contains a quater- erogeneously distributed: (1) M1 receptors are present nary ammonium group that gives ACh a permanent in brain, exocrine glands, and autonomic ganglia. The anionic transmembrane domain, G protein–coupled receptors, site contains a negatively charged amino acid that binds and they are structurally and functionally unrelated to the positively charged quaternary ammonium group of nicotinic ACh receptors. This probably serves to ceptors by an agonist triggers the release of an intracel- bring the ester linkage of ACh close to the esteratic site lular G-protein complex that can speciﬁcally activate of the enzyme. Fortunately, residue, which is made more reactive by hydrogen the cellular responses elicited by odd- versus even- bonding to a nearby histidine residue. The nucleophilic numbered receptor subtypes can be conveniently dis- oxygen of the serine reacts with the carbonyl carbon of tinguished. During this re- produces an inosine triphosphate (IP3) mediated re- action, choline is liberated and an acetylated enzyme is lease of intracellular calcium, the release of diacylglyc- formed. The latter intermediate is rapidly hydrolyzed to erol (which can activate protein kinase C), and stimula- release acetic acid and regenerate the active enzyme. These receptors are primarily The entire process takes about 150 microseconds, one of responsible for activating calcium-dependent responses, the fastest enzymatic reactions known. AChE (also known as true, speciﬁc, or lyl cyclase, and activation of M2 receptors opens potas- erythrocyte cholinesterase) is found at a number of sites sium channels. The opening of potassium channels hy- in the body, the most important being the cholinergic perpolarizes the membrane potential and decreases the neuroeffector junction. Here it is localized to the pre- excitability of cells in the sinoatrial (SA) and atrioven- junctional and postjunctional membranes, where it rap- tricular (A-V) nodes in the heart. These limitations have been circumvented in Anionic site Esteratic site part by the development of three choline ester derivatives of ACh: methacholine (Provocholine), carbachol (Isopto Carbachol, Miostat) and bethanechol (Urecholine). This modiﬁcation greatly increases its selectivity for muscarinic receptors (CH3)3N CH2 CH2 OH CH3 C O relative to nicotinic receptors, and it renders methacholine O H resistant to the pseudo-ChE in the plasma and decreases its susceptibility to AChE, thereby increasing its potency and duration of action compared to those of ACh. Carbachol differs from ACh only in the substitution of a carbamoyl group for the terminal methyl group of ACh. This substitution makes carbachol completely resistant to OH degradation by cholinesterases but does not improve its O selectivity for muscarinic versus nicotinic receptors. CH3 C O H Bethanechol combines the addition of the methyl group and the substitution of the terminal carbamoyl group, pro- ducing a drug that is a selective agonist of muscarinic re- FIGURE 12. Simpliﬁed scheme of ACh hydrolysis at the active center of All of these drugs are very hydrophilic and mem- ACh. Rectangular area represents the active center of the brane impermeant because they retain the quaternary enzyme with its anionic and esteratic sites. The broken line at right Pilocarpine is a naturally occurring cholinomimetic represents the initial interaction between the serine oxygen alkaloid that is structurally distinct from the choline es- of the enzyme and the carbonyl carbon of ACh. It is a tertiary amine that crosses membranes rela- linkage is broken, choline is liberated, and an acetylated tively easily. Finally, the cornea of the eye, and it can cross the blood-brain bar- acetylated intermediate undergoes hydrolysis to free the rier. Muscarine is an alkaloid with no therapeutic use, but it can produce dangerous cholinomimetic stimulation following inges- tion of some types of mushrooms (e. There is no reuptake sys- Basic Pharmacology of the Directly tem in cholinergic nerve terminals to reduce the con- Acting Parasympathomimetic Drugs centration of ACh in a synaptic cleft, unlike the reup- Methacholine, bethanechol, and pilocarpine are selec- take systems for other neurotransmitters such as tive agonists of muscarinic receptors, whereas carbachol dopamine, serotonin, and norepinephrine. Therefore, in- and ACh can activate both muscarinic and nicotinic re- hibition of AChE can greatly prolong the activation of ceptors. This apparent preference for nonspeciﬁc cholinesterase) has a widespread distribu- muscarinic receptors can be attributed to the greater ac- tion, with enzyme especially abundant in the liver, cessibility and abundance of these cholinoreceptors where it is synthesized, and in the plasma. It does, however, Cardiovascular Effects play an important role in the metabolism of such clini- cally important compounds as succinylcholine, pro- Low doses of muscarinic agonists given intravenously caine, and numerous other esters. Activation of these receptors causes the endothe- and reduces cAMP levels, slowing the rate of depolar- lial cells to synthesize and release nitric oxide. Nitric ox- ization and decreasing the excitability of SA node and ide can diffuse into neighboring vascular smooth muscle A-V ﬁber cells.
These deficits can include both inadequate sensation proven 100 mg voveran sr, such as partial or total blindness or the distorted or altered sensation that can occur in various pain syndromes purchase voveran sr 100 mg overnight delivery. Clearly cheap voveran sr 100 mg with amex, severe deficits arise from blindness and hearing deficits discount voveran sr 100mg on line, leading to impetus for development of augmentative devices such as cochlear prostheses. Even though the conditions are neither life-threatening nor significant in terms of loss of function, patients commonly seek treatments for relief. For example, periph- eral nerve, spinal cord and midbrain/thalamic stimulation have been used commonly for more than 30 years for the relief of pain, in part driven by patient suffering and need for treatment. For example, patients with hemisphere or brainstem strokes may show hemiplegia (inability to move on one side), while patients with spinal cord injuries commonly have upper or lower extremity impairments or both. While lower extremity impairments interfere with walking, the inability can often be overcome by simple use of a wheelchair or other assistive device. Attempts to achieve com- puter-generated walking through direct muscle stimulation (known as functional electrical stimulation or FES) have shown some ability in aiding muscle movement. Upper extremity and hand function deficits are much more devastating and preclude most tasks; they also have minimal rehabilitation potential and usually require significant assistance even for activities of daily living. Another type of deficit is caused by ALS, a disease that may also affect the brainstem and upper cervical spinal cord, resulting in intact cognition but impaired speech and hand motion — a severely debilitating combination for interactions with the external world. Peripheral injuries and congenital defects, including lack of upper extremities (iatrogenic or traumatic amputation, for example) may also prevent translation of thoughts into actions. For all these conditions, a residual peripheral output such as a small muscle contraction could be useful for device control, but only in a highly limited format and with minimal information transfer for complex output of thoughts. Because most human interac- tions consist of speech and vocalization, persons with communication deficits may have severe problems defining and stating even their basic daily living needs. Most current approaches to enhancement of communication problems depend on residual output such as muscle contractions that can then trigger devices to achieve external speech or virtual choice output, but such devices are highly limited in terms of letter and word throughput. Conceivably, a highly efficient, more direct connection among people could bypass the need for vocaliza- tion altogether. Augmentation beyond normal innate human function has been a common thread in the entire history of human development. For example, eyeglasses, laser keratotomy, microscopes, and telescopes all enhance vision beyond normal ability. Most plastic surgery procedures, joint replacements, and other medical approaches are not always performed only to treat medical conditions; they are intended to improve function beyond what a patient normally experiences. The difference between ordinary augmentations and neuroprosthetics lies in using devices to mimic inherent brain signals for enhanced or direct sensory input into the brain, and decoding of normal brain signals for alternate channeling of motor output function. Although a variety of methods have been utilized, many current (and projected) neuroprosthetic devices are implanted directly into the brain. Implantation has the advantage of bypassing peripheral inputs and outputs, hence decreasing the time © 2005 by CRC Press LLC between signal and brain response. For example, a motor output could be channeled directly to a device for enhancing motor control on a microscopic, macroscopic, or larger-than-human level, resulting in considerable scaling of effort, far beyond the capabilities of the ordinary human motor system. Additionally, the time to response could be far less with direct inputs and outputs into the brain by speeding up a reflex loop, assuming the brain can keep pace with such external devices. Time and physical scaling enhancements have obvious practical importance for extending human control to environments that are hostile to biological tissue or, for example, aiding space exploration by decreasing delay in transmission. As argued in a recent article by noted ethicist Arthur Caplan,1 such augmentation is a natural extension of the long human interest in tool use and extends our understanding of the universe beyond our meager physical senses and motor capabilities although it potentially requires brain implants to access the nervous system directly. The main limitations of a scheme for enhancing brain function are deciphering inherent brain encoding of sensation and motor function and achiev- ing a stable interface between electrodes and the nervous system at a sufficiently small level to be meaningful for brain components, particularly axons and neurons on the micron scale. Excessive stimulation or recording interfaces may lead to unrealistic stimulation of multiple nervous elements, resulting in less-than-specific responses or noise and ranging across too many neural elements for decoding of neural output. Since enhancement of human performance and nervous system function are commonly employed now, how would such system be perceived and used in a wider arena? Clearly, the ethical issues point to self-determination and use, in other words, coercion to use a device would argue strongly against self-determination and free choice, particularly for implantable devices. Another ethical aspect to consider is universal access to such self-enhancements to prevent unfair advantage. Of course, most current self-enhancement advantages (expensive colleges, SAT preparation courses, etc. Whoever applies augmentation technology should bear these ethical principles in mind, particularly for implantable devices, to avoid coercion (as with other types of medical care), maintain individual self-determination, and allow the widest access possible.