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Instead 2.5 ml xalatan overnight delivery symptoms zollinger ellison syndrome, the formed (yellow area in the schematic draw- cells have the property of sequestering polar ing cheap 2.5 ml xalatan free shipping symptoms ms, bottom left) and acts as a continuous lipids that assemble into layers within the barrier between the two spaces separated extracellular space (semicircular inset buy 2.5 ml xalatan otc medications zetia, cen- by the cell layer—in the case of the gut cheap xalatan 2.5 ml with visa symptoms 9 weeks pregnancy, the ter right). In this manner, a continuous phos- intestinal lumen (dark blue) and interstitial pholipid barrier arises also inside squamous space (light blue). The ef ciency with which epithelia, although at an extracellular loca- such a barrier restricts exchange of substan- tion,unlikethatofintestinalepithelia. A ces can be increased by arranging these oc- similar barrier principle operates in the mul- cluding junctions in multiple arrays, as for tilayered keratinized squamous epithelium instance in the endothelium of cerebral of the skin. The connecting proteins (con- Thepresenceofacontinuousphospholi- nexins) furthermore serve to restrict mixing pid layer again means that only lipophilic of other functional membrane proteins (car- drugs can enter the body via squamous epi- rier molecules, ion pumps, ion channels) that thelia. Epithelial thickness, which in turn occupy specific apical or basolateral areas of dependsonthedepthofthestratum cor- the cell membrane. Examples of drugs that can be intestinal mucosa–blood barrier that a drug conveyed via the skin into the blood include must cross during its enteral absorption. External barriers of the body Nonkeratinized Ciliated epithelium squamous epithelium Epithelium with Keratinized squamous brush border epithelium Luellmann, Color Atlas of Pharmacology © 2005 Thieme 24 Distribution in the Body proteins such as insulin (G: insulin storage ‡ Blood–Tissue Barriers granule). Penetrability of macromolecules is Drugs are transported in the blood to differ- determined by molecular size and electric ent tissues of the body. Fenestrated endothelia are found in their sites of action, they must leave the the capillaries of the gut and endocrine bloodstream. The endo- path requires specific physicochemical prop- thelial cells are “riveted” to each other by erties (p. Thus, the Z in the electron micrograph, upper left) blood–brain barrier is permeable only to cer- such that no clefts, gaps, or pores remain tain types of drugs. Perme- diameter) facing Disse’s spaces (D) and ability of the capillary wall to drugs is deter- where neither diaphragms nor basement mined by the structural and functional char- membranes impede drug movement. Although the cells are tightly con- nected bycontinuous junctions, they possess pores (arrows in electron micrograph, lower left) that are closed only by diaphragms. Both the diaphragm and basement mem- brane can be readily penetrated by substan- ces of low molecular weight—the majority of drugs—but less so by macromolecules, e. An ability to penetrate lipid bilayers is a The distribution of drugs in the body can prerequisite for the absorption of drugs, be greatly changed by transport glycopro- their entry into cell or cellular organelles, teins that are capable of moving substances and passage across the blood–brain barrier. Lipophilic substances (red er, they can cause drug resistance by pre- dots) may enter the membrane from the venting drugs from reaching effective con- extracellular space (area shown in ochre), centrations at intracellular sites of action. When of permeation depend on the relative con- new vesicles are pinched off, substances dis- centrations inthefluidphases and the mem- solved in the extracellular fluid are engulfed brane. The steeper the gradient (concentra- and then ferried through the cytoplasm, un- tion difference), the more drug will be dif- less the vesicles (phagosomes) undergo fu- fusing per unit of time (Fick’s law). The lipid sion with lysosomes to form phagolyso- membrane represents an almost insur- somes and the transported substance is me- mountable obstacle for hydrophilic substan- tabolized. Some drugs may penetrate drug first binds to membrane surface recep- membrane barriers with the help of trans- tors (1, 2) whose cytosolic domains contact port systems (carriers), irrespective of their special proteins (adaptins, 3). Drug–receptor physicochemical properties, especially lipo- complexes migrate laterally in the mem- philicity. As a prerequisite, the drug must brane and aggregate with other complexes have af nity for the carrier (blue triangle by a clathrin-dependent process (4). The af- matching recess on “transport system”) fected membrane region invaginates and and, when bound to the carrier, be capable eventually pinches off to form a detached of being ferried across the membrane. The clathrin and adaptin coats brane passage via transport mechanisms is are shed (6), resulting in formation of the subject to competitive inhibition by another “early” endosome (7). Inside this, proton substance possessing similar af nity for the concentration rises and causes the drug–re- carrier. These membrane L-dopa uptake by L-amino acid carrier across sections recirculate to the plasmalemma the blood–intestine and blood–brain bar- (9), while the endosome is delivered to the riers (p. Membrane permeation: vesicular uptake, and transport 1 9 2 8 pH 5 3 Ligand Plasmalemma 4 Receptor 10 Clathrin 6 Adaptins 7 5 Vesicular transport Lysosome Phagolysosome Extracellular Intracellular Extracellular Luellmann, Color Atlas of Pharmacology © 2005 Thieme 28 Distribution in the Body Solid substances and ‡ Possible Modes of Drug Distribution structurally bound water Following its uptake into the body, the drug is distributed in the blood (1)andthroughit to the various tissues of the body. Distribu- 40% tion may be restricted to the extracellular 20% space (plasma volume plus interstitial space) 40% (2) or may also extend into the intracellular space (3). Certain drugs may bind strongly to tissue structures so that plasma concentra- tions fall significantly even before elimina- tion has begun (4). Intracellular water Extracellular water and erythrocytes After being distributed in blood, macro- molecular substances remain largely con- fined to the vascular space, because their ume is large in premature or normal neo- permeation through the blood–tissue bar- nates (up to 50% of body water), and smaller rier,orendothelium,isimpeded,evenwhere in the obese and the aged. This property is The concentration (c) of a solution corre- exploited therapeutically when loss of blood sponds to the amount (D) of substance dis- necessitates refilling of the vascular bed, for solved in a volume (V); thus, c = D/V. The vascular space is, moreover, tion (c) are known, a volume of distribution predominantly occupied by substances (V) can be calculated from V = D/c. Unbound, free distribution in the body is assumed in its drug may leave the bloodstream, albeit with calculation. Homogeneous distribution will varying ease, because the blood–tissue bar- not occur if drugs are bound to cell mem- rier (p. These re- organelles (6)orarestored within organelles gional differences are not illustrated in the (7). Lipophilic substances diffuse through the cell membrane and, as a result, achieve a uniform distribution in body fluids (3). On a percentage basis, interstitial fluid vol- Luellmann, Color Atlas of Pharmacology © 2005 Thieme Possible Modes of Drug Distribution 29 A. Compartments for drug distribution 1 3 Intravascular Intravascular and Extra- and Tissue binding interstitial intracellular Plasma Interstitium 6% 25% 4% 65% Erythrocytes Aqueous spaces of the organism Intracellular space Lysosomes Mito- chondria Nucleus Cell membrane 5 Luellmann, Color Atlas of Pharmacology © 2005 Thieme 30 Distribution in the Body glomerular filtration. When concentrations ‡ Binding to Plasma Proteins of free drug fall, drug is resupplied from Having entered the blood, drugs may bind to binding sites on plasma proteins. Binding the protein molecules that are present in to plasma protein is equivalent to a depot abundance, resulting in the formation of in prolonging the duration of the effect by drug–protein complexes. If two substances min and, to a lesser extent, β-globulins and have af nity for the same binding site on acidic glycoproteins. Onedrugmaydisplaceanother ing globulin) serve specialized functions in from its binding site and thereby elevate the connection with specific substances. The de- free (effective) concentration of the dis- gree of binding is governed by the concen- placed drug (a form of drug interaction). Clearance rates ing sites for anionic and cationic ligands, but of these substances can be used to determine van der Waals forces also contribute (p. Protein binding is of great importance because it is the concentration of free drug that deter- mines the intensity of the effect. At a given total plasma concentration (say, 100 ng/ml) the effective concentration will be 90 ng/ml for a drug 10% bound to protein, but 1 ng/ml for a drug 99% bound to protein. The reduc- tion in concentration of free drug resulting from protein binding affects not only the intensity of the effect but also biotransfor- mation (e. Importance of protein binding for intensity and duration of drug effect Drug is not Drug is bound strongly bound to plasma to plasma proteins proteins Effect Effect Effector cell Effector cell Biotransformation Biotransformation Renal elimination Renal elimination Plasma concentration Plasma concentration Free drug Bound drug Free drug Time Time Luellmann, Color Atlas of Pharmacology © 2005 Thieme 32 Drug Elimination enon is generally referred to as genetic poly- ‡ The Liver as an Excretory Organ morphism of biotransformation.

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Constipation Joint National Committee on Prevention xalatan 2.5 ml overnight delivery symptoms 3 days past ovulation, Detection generic xalatan 2.5 ml with visa medicine expiration, Evaluation and Treatment of High Blood Pressure buy xalatan 2.5 ml overnight delivery treatment eating disorders. What additional information would be useful in determining tee of the National Cholesterol Education Program xalatan 2.5 ml low cost useless id symptoms. Implications of the extent of the patient’s osteoporosis and the need for recent clinical trials for the National Cholesterol Education Program aggressive therapy? Global strategy for diagnosis, management, and prevention of chronic obstructive lung disease executive summary. What nondrug therapies might be useful for this patient’s and treatment of postmenopausal osteoporosis: 2001 edition, with osteoporosis? What information (signs, symptoms, laboratory values) indi- Deferred cates the presence and severity of rheumatoid arthritis? What clinical and laboratory parameters are necessary to evaluate See Table 96-1 the patient’s drug therapy? What information should be provided to the patient to enhance í Chest X-Ray adherence, ensure successful therapy, and minimize adverse No fluid, masses, or infection; no cardiomegaly effects? Guidelines for the management of rheumatoid Donald Abernathy is a 73-year-old man who presents to the arthritis: 2002, Update. Etanercept therapy complaining of increasing pain in his lower back, hips, and right in rheumatoid arthritis. Therapeutic effect of mg tablets, two tablets four times daily, and has been taking more the combination of etanercept and methotrexate compared with each than prescribed over the last few weeks. He has infliximab and methotrexate therapy for early rheumatoid arthritis: a been adherent to all other drug therapies. A multicentre, double blind, on excess weight and developed many medical problems that are randomized, placebo controlled trial of anakinra (Kineret), a recombi- frustrating him. Sulfa—hives • Design an appropriate pharmacotherapeutic regimen for treat- Egg products ing osteoarthritis, taking into account a patient’s other medical problems and drug therapy. What feasible pharmacotherapeutic alternatives are available stool in rectal vault for treatment of this patient’s osteoarthritis? What drug, dosage form, schedule, and duration of therapy are rotation >45°; both hips tender to palpation; right knee (+) crepi- best for treating this patient’s osteoarthritis? What clinical and laboratory parameters are necessary to evaluate ally except for slightly diminished Achilles reflexes bilaterally; no the therapy for achievement of the desired therapeutic outcome focal deficits; gait impaired secondary to hip and knee pain. What information should be provided to the patient to enhance adherence, ensure successful therapy, and minimize adverse effects? If not, • Recognize major risk factors for developing gout in a given pa- what is an appropriate next step of treatment? Which form of glu- • Develop a pharmacotherapeutic plan for a patient with acute cosamine is best to suggest to patients? The patient tells you that one time his friend received an injection into his knee that really helped his arthritis. When should intra- • Identify patients in whom maintenance therapy for gout and articular injections be considered, and what are some of their hyperuricemia is warranted. Patients whose arthritis is poorly or inadequately controlled often turn to alternative, homeopathic, or herbal remedies for relief. Identify one site that you think pro- Nathan Vance is a 66-year-old man with a history of dyslipidemia vides misleading or potentially dangerous information to patients. He relates no trauma or injury systematic approach to assessing and treating pain in order to to the ankle and has not exerted himself more than usual in the achieve total (or near-total) pain relief, avoid wasting resources, and recent past. Glucosamine, chondroitin sulfate, Simvastatin and atorvastatin (both caused severe muscle aches, and and the two in combination for painful knee osteoarthritis. He relates feeling “hot and flushed” occasionally after taking his niacin, but this has not been a major problem for him. Should chronic treatment to decrease the patient’s serum uric Clear to auscultation bilaterally, symmetric movement with inspira- acid level be initiated at this time? Considering the patient’s information, what drug, dosage form, schedule, and duration of therapy are best in this case? Joint is exquisitely painful with Patient Education patient relating the pain as currently a 10/10 (on a 1–10 scale with 6. What information should be provided to the patient to enhance “1” being no pain and “10” being the worse pain the patient has ever adherence, ensure successful therapy, and to avoid adverse effects? After consultation with you, í Labs the patient’s physician decides against maintenance therapy to Na 138 mEq/L Hgb 15. Primary presentation of acute gouty arthritis may be most appropriate, because it has been shown to signifi- cantly decrease serum uric acid levels? List antihyperuricemic agents that are available in the United States and their relative advantages and disadvantages. Fenofibrate enhances clinical endpoint for discontinuing the drug, as these side effects tend urate reduction in men treated with allopurinol for hyperuricaemia to occur prior to the more severe adverse effects of colchicine- and gout. Other ocular history includes severe myopia since child- After completing this case study, students should be able to: hood, history of dry eyes, and history of contact lens wear. Depression as a consequence of chronic open-angle glaucoma and worsening of vision after completion of his PhD program • Select and recommend agents from different pharmacologic class- S/P ultrasonic renal lithotripsy secondary to nephrolithiasis associ- es when indicated and provide the rationale for drug selection. Drank four cans of beer per day for 3 years during postgrad- • Explain and discuss possible adverse drug reactions with pa- uate study. Comparison of the retina in a patient with a healthy optic nerve (left) and in a patient with glaucoma and a large cup with a disc hemorrhage, typical of chronic open-angle glaucoma (right). No cataracts eyes; conjunctiva without injection; normal tear break-up, did not stain with fluorescein; cornea clear and smooth; anterior 4. Depression associated with chronic open-angle glaucoma without neovascularization or abnormality; no mass/nodules; í Plan filtering bleb is visible at 11 o’clock meridian. What information (signs, symptoms) indicates the presence or tone, and sensation are intact bilaterally. Are phosphodiesterase-5 inhibitors such as sildenafil safe for Sensation was intact and symmetric to pinprick, proprioception, and patients with high intraocular pressure? What clinical and laboratory parameters are necessary to evaluate • Classify a patient’s allergic rhinitis based on the signs and the therapy for achievement of the desired therapeutic outcome symptoms of the disease. What information should the patient receive about the disease of rhinitis with respect to efficacy and safety. What is the mechanism of action of these antimetabolites in tra- beculectomy pressure-lowering surgery? Perform a literature search and explain the rationale for using í Chief Complaint nimodipine and pentoxifylline in advanced open-angle glau- “My nose is stopped up and I can’t sleep at night. Compare the advantages and disadvantages of using this always tired, and now my eyes are itchy and watery all the time. Compliance and persistency in glaucoma follow-up symptoms have occurred off and on since she was a child, worsen- treatment. Response of filtered eyes to but she does have an occasional nonproductive cough that gets digital ocular pressure. A randomized double-masked Anterior cruciate ligament reconstruction at age 16 crossover study comparing latanoprost 0.

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He had no medical degree; he burned the classical medical works (Galen buy discount xalatan 2.5 ml on-line medications you cant drink alcohol with, Avicenna) and discount 2.5 ml xalatan fast delivery symptoms nausea headache, of course cheap 2.5 ml xalatan mastercard medications not covered by medicare, pharmacology generic 2.5 ml xalatan overnight delivery treatment integrity checklist. There are three key decision before his lectures in Basle (Switzerland) and had to leave the city points along the way: following a dispute about fees with a prominent churchman. Selecting the molecular target you want the drug to act because he was thrown down a steep incline by ‘hitmen’ employed by on to produce the desired effect. This has turned out not to be the case since it is clearly pharmacoproteomics (understanding of and drug effects important to understand both the function of the target on protein variants) remain high, but the applicability will and the nature of the interaction of the chemical drug with not be universal. The ability accurately to subclassify ously not been possible (or that does safely what could based on common genetic variation is less clear. This is most advanced in the field of gramme is founded on precise knowledge of the biological cancer (usually targeting somatic changes in cancers) processes it is desired to change. The commercial rewards and increasingly in the field of the pharmacogenetics of ofasuccessfulproductarepotentiallyenormousandprovide safety. Most projects in drug discovery and development cal trial programmes with well-defined patient groups fail. Indeed the chances of making it through from target (based on phenotypic and genotypic characterisation), bet- selection to having a medicine on the market are under 1 ter understanding of the pharmacokinetics and dynamics in 100. I then want approach also led to a loss of integration of the to know that it does what I need it to do in terms of the established specialities (chemistry, biochemistry, effect on disease. Theoretically, new drugs could be targeted at selected • Post-licensing (marketing) studies of safety and groups of patients based on their genetic make-up. The (critical) phase of progress from the laboratory to humans is often termed translational science or experimental 3Culliton B J 1994 Nature Medicine 1:1 [editorial]. It was defined as ‘the application of biomedical 30 Discovery and development of drugs Chapter | 3 | research (pre-clinical and clinical), conducted to support eliminate their undesired, properties to create highly selec- drugdevelopment,which aids inthe identificationofthe ap- tive targeted compounds. In principle all molecular struc- propriatepatientfortreatment(patientselection),thecorrect tures capable of binding to a single high-affinity site can dose and schedule to be tested in the clinic (dosing regimen) be modelled. Successful developments these are large robotic screens but newer technologies, in- (1% of compounds that proceed to full test eventually be- cluding use of small molecules using coding tags, allow come licensed medicines) must carry the cost of the failures 5 miniaturisation of the process. It is also obvious that such programmes are likely which is the starting point for medicinal chemistry ‘lead op- to be carried to completion only when the organisations timisation’, depends on the quality of the molecules in the and the individuals within them are motivated overall by compound collection and the nature of the biochemical the challenge to succeed and to serve society, as well as target used for the screen. A previous edition of this chapter included a quote from a paper I wrote from my time in academia and Fragments. If the crystal structure of the protein target is I leave it here: known it is possible to screen small fragments of potential drugs to find those that bind and where they bind. It is then Let us get one thing straight: the drug industry works possible to construct a drug by adding fragments. Unfortunately most drugs fall short 7 successful new medicines of the last few years have been of this ideal. The drug may fail at any used as models for human disease as well as for production stage, including the ultimate, i. It may also fail (due to adverse effects) within the first year after marketing, which constitutes Antisense approaches. Nucleic acid approaches are being a catastrophe (in reputation and finance) for the developer as well as developed to silence gene expression and therefore reduce for some of the patients. Pirated copies of full regulatory dossiers have substantial black market value to competitor companies, who have the expression of culprit proteins. There are various differ- used them to leapfrog the original developer to obtain a licence for ent ways of achieving this including antisense, locked their unresearched copied molecule. Nonetheless, where the treatment aim is 31 Section | 1 | General Sources of compounds Therapeutic targets Chemical libraries Traditional medical uses of natural products Historical compound collections Natural product libraries Combinatorial libraries Empirical understanding of physiology and pathology Rational synthesis Molecular cloning of receptors and signalling molecules Antisense oligonucleotides Genomics Drug discovery screening assays Lead optimisation and candidate selection Drug development Fig. Different types of chemical compounds (top left) are tested against bioassays that are relevant to therapeutic targets, which are derived from several possible sources of information (right). The initial lead compounds discovered by the screening process are optimised by analogue synthesis and tested for appropriate pharmacokinetic properties. The candidate compounds then enter the development process involving regulatory toxicology studies and clinical trials. Understanding of the molecular where a liver effect is desired, it is clear that this ap- basis of immune responses has allowed the definition proach works and provides a potentially attractive ap- of mechanisms by which cellular function is altered by a proach to targeting those proteins or protein–protein legion of local hormones or autacoids in, for example, interactions that are intractable to a small molecule, pep- infections, cancer, autoimmune diseases, organ transplant tide or antibody approach. It is always the case the methods of delivery and the safety and efficiency of that the animal model is never a true model of the vectors used to deliver the genes. So far success has human disease and can only model parts of the been seen in the treatment of certain rare haemopoetic disease process. The trend in industry is to move disorders and genetic immunodeficiency states where fast to the clinic and not to rely too heavily on thegenetransfercanbedoneexvivoandthemodified animal models. Stem cells are impacting drug discovery as they Multinational pharmaceutical companies now scour potentially provide a source of human cells, or even dis- the world for leads from microorganisms (in soil or ease-specific human cells that can be used for screening sewage or even from insects entombed in amber 40 and safety testing. However, the promise is of regenerative luxuriant natural resources) are prominent targets treatments based either on stem cell replacement or chem- in this search and have justly complained of ical stimulation of endogenous stem cells. Many now require 32 Discovery and development of drugs Chapter | 3 | formal profit-sharing agreements to allow such 9 searches. The problem with natural product drug discovery is often that identifying the Pharmacodynamics – to investigate the actions relating to precise active ingredient is hard and the molecules the proposed therapeutic use. This is particularly Pharmacokinetics – the study of the fate of the active true in China where traditional medicines are being substance and its metabolites within the organism (absorp- re-evaluated for effects. The most notable example in tion, distribution, metabolism and excretion of these sub- recent years is the rediscovery of artemisinin for malaria stances). However, such approaches are very unlikely to be commercially • Acute toxicity: single-dose studies that allow qualitative successful in a world that rightly demands true and quantitative assessment of toxic reactions. This includes the • Random screening of synthesised and natural identification of potential target organs and exposure– products. A recent depends on the conditions of clinical use and is defined example is rituximab, a monocloncal antibody that by Regulatory Agencies (Tables 3. Initially developed for the treatment of B Genotoxicity – to reveal the changes that a drug may cause cell lymphoma it was found to be effective for in the genetic material of individuals or cells. Mutagenic suppressing B cell autoimmunity in diseases such substances present a hazard to health because exposure as rheumatoid arthritis. An impure, unstable drug or formulation is use- (pharmacotoxicological) studies must be carried out in conformity with less. In Europe, regulations ensure that all tests on storage in hot, damp climates are vital to therapeutics. Much of the early work in drug discovery is spent try- tests provided that the test results are of comparable quality and usefulness for the purpose of safety evaluation. The pharmacological ing to identify the right molecule with the appropriate and toxicological tests must demonstrate the potential toxicity of the physical and chemical properties to make it reliable as a product and any dangerous or undesirable toxic effects that may occur medicine. The studies must also demonstrate the pharmacological properties of 8Serendipity is the faculty of making fortunate discoveries by general the product, in both qualitative and quantitative relationship to the sagacity or by accident; the word derives from a fairytale about three proposed use in human beings. Single dose 2 weeks2 2 weeks Reproductive and developmental toxicity – these tests study effects on adult male or female reproductive func- Up to 2 weeks 2 weeks 2 weeks tion, toxic and teratogenic effects at all stages of develop- Up to 1 month 1 month 1 month ment from conception to sexual maturity and latent effects, when the medicinal product under investigation Up to 3 months 3 months 3 months has been administered to the female during pregnancy.

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The most prominent feature of the ischium is a large tuberosity (the ischial tuberosity) on the posteroinferior In the clinic aspect of the bone purchase 2.5 ml xalatan visa medicine youth lyrics. This tuberosity is an important site for Bone marrow biopsy the attachment of lower limb muscles and for supporting In certain diseases (e buy 2.5 ml xalatan overnight delivery medications an 627. The iliac crest lies close to The sacrum generic xalatan 2.5 ml online treatment 4 pimples, which has the appearance of an inverted tri­ the surface and is easily palpated 2.5 ml xalatan free shipping medications grapefruit interacts with. The bone marrow is aspirated and viewed under a lateral surfaces of the bone bears a large L-shaped facet for microscope. Posterior to obtained in this way to provide information about the facet is a large roughened area for the attachment of bone metabolism. The superior 444 surface of the sacrum is characterized by the superior Regional anatomy • Pelvis Superior articular process Ala Posterior sacral foramina B articular process Anterior sacral foramina Promontory Coccyx Transverse process Articular facet for hip bone A c Fig. The anterior edge of the vertebral body projects The small terminal part of the vertebral column is the forward as the promontory. The anterior surface of the coccyx, which consists of four fused coccygeal vertebrae sacrum is concave; the posterior surface is convex. The base of the coccyx is directed supe­ lateral to the position of the intervertebral foramina and riorly. The superior surface bears a facet for articulation lateral to the bifurcation of spinal nerves into posterior and with the sacrum and two horns, or cornua, one on each anterior rami, the posterior and anterior rami of spinal side, that project upward to articulate or fuse with similar nerves Sl to S4 emerge from the sacrum through separate downward-projecting cornua from the sacrum. There are four pairs of anterior sacral foram­ cesses are modifed superior and inferior articular pro­ ina on the anterior surface of the sacrum for anterior rami, cesses that are present on other vertebrae. Each lateral and four pairs of posterior sacral foramina on the pos­ surface of the coccyx has a small rudimentary transverse terior surface for the posterior rami. Verte­ continuation of the vertebral canal that terminates as the bral arches are absent from coccygeal vertebrae; therefore sacral hiatus. The sacrum articulates superiorly with the lumbar part of There are three bony rings and fourfbro-osseous rings. Fractures of the pelvis may occur in isolation; The lumbosacral joints are reinforced by strong iliolum­ however, they usually occur in trauma patients and bar and lumbosacral ligaments that extend from the warrant special mention. A large hematoma may be produced, which Sacro-iliacjoints can compress organssuch asthe bladderandthe ureters. This blood loss may occur rapidly, reducing the The sacro-iliac joints transmit forces from the lower limbs circulating blood volume and, unless this is replaced, the to the vertebral column. The joints ofen Anterior longitudinal ligament Anterior longitudinal ligament Iliolumbar ligament Intervertebral foramen for Zygapophysial joint For posterior sacro-iliac ligament For interosseous sacro-iliac ligament Interverebral disc Ilium A B Fig. As a consequence, the pelvic inlet, whichmarks is surrounded by interwoven layers of collagen fbers and the entrance to the pelvic cavity, is tilted to face anteriorly, the two major ligaments associated with it are: and the bodies of the pubic bones and the pubic arch are positioned in a nearly horizontal plane facing the ground. In the clinic Common problems with the sacro-iliac joints • The pelvic inlet in women is circular {Fig. The more circular shape is partly caused by the degenerative changes may occur and cause pain and less distinct promontory and broader alae in women. Pectineal line Pubic crest Anterior superior iliac spine Pubic tubercle Pubic symphysis Inferior pubic ligament Ischial ramus Obturator foramen Inferior pubic ramus Fig. The angle formed by the pubic arch can be approximated by the angle between the thumb and index fnger for women and the angle between the index fnger and middle fnger for men as shown in the insets. True pelvis Sacro-iliac joint Margin of ala Promontory The true pelvis is cylindrical and has an inlet, a wall, and an outlet. The inlet is open, whereas the pelvic floor closes the outlet and separates the pelvic cavity, above, from the perineum, below. Pelvic inlet The pelvic inlet is the circular opening between the abdom­ inal cavity and the pelvic cavity through which structures traverse between the abdomen and pelvic cavity. The margin of the pelvic inlet then crosses the sacro-iliacjoint and continues along the linea termina­ lis. They also convert the greater coccyx, the pelvic bones inferior to the linea terminalis, two and lesser sciatic notches of the pelvic bone into foramina ligaments, and two muscles. Ligaments of the pelvic wall • The greater sciatic foramen lies superior tothe sacro­ The sacrospinous and sacrotuberous ligaments (Fig. These • The sacrotuberous ligament is also triangular and is muscles originate in the pelvic cavity but attach peripher­ superfcial to the sacrospinous ligament. Laterally, the apex of the originates from the deep surface of the obturator mem­ ligament is attached to the medial margin of the ischial brane and from associated regions of the pelvic bone that tuberosity. Greater sciatic foramen Vertebral column Lesser sciatic foramen Ligaments prevent upward tilting of sacrum Greater foramen Sacrospinous ligament ligament Sacrotuberous Sacrotuberous ligament Obturator canal ligament Lesser sciatic Obturator membrane foramen A B Fig. In addition, this muscle The obturator internus forms a large part of the antero­ separates the greater sciatic foramen into two regions, one lateral wall of the pelvic cavity. Vessels and nerves cours­ ing between the pelvic cavity and the gluteal region pass Piriformis through these two regions. The piriformis is triangular and originates in the bridges of bone between the four anterior sacral foramina. It passes 451 Pelvis and Perineum pelvic bone, the sacrotuberous and the sacrospinous liga­ Apertures inthe pelvic wall ments, and the spine of the ischium. Each lateral pelvic wall has three major apertures through The piriformis muscle passes through the greater sciatic which structures pass between the pelvic cavity and other foramen, dividing it into two parts. The obturator nerve and vessels pass Lesser sciatic foramen from the pelvic cavity to the thigh through this canal. The lesser sciatic foramen is formed by the lesser sciatic notch of the pelvic bone, the ischial spine, the sacrospinous Greater sciatic foramen ligament, and the sacrotuberous ligament (Fig. The greater sciatic foramen is a major route of communi­ The tendon of the obturator internus muscle passes cation between the pelvic cavity and the lower limb through this foramen to enter the gluteal region of the (Fig. Superior gluteal nerve and vessels Greater sciatic foramen, above and below piriformis muscle Sciatic nerve, inferior gluteal, posterior femoral cutaneous, and quadratus femoris nerves and vessels Pudendal nerve and internal pudendal vessels and nerve to obturator internus Lesser sciatic foramen Obturator canal - obturator nerve and vessels Fig. Together, the elements perineum (below the pelvicfoor), by frst passing out of the on both sides form the pubic arch. Terminal parts of the urinary and gastrointestinal tracts and the vagina pass through the pelvic outlet. Pelvic outlet The area enclosed by the boundaries of the pelvic outlet The pelvic outlet is diamond shaped, with the anterior and below the pelvic floor is the perineum. These measurements include: • the sagittal inlet (between the promontory and the top of the pubic symphysis), • the maximum transverse diameter of the inlet, • the bispinous outlet (the distance between ischial spines), and • the sagittal outlet (thedistance between the tip of the coccyx and the inferior margin of the pubic symphysis). These measurements can be obtained using magnetic resonance imaging, which carries no radiation risk for the fetus or mother (Fig. Pelvic foor the pelvic cavity and the gluteal region of the lower The pelvic floor is formed by the pelvic diaphragm and, in limb; and the anterior midline, the perineal membrane and the • the lesser sciatic foramen is situated below the pelvic muscles in the deep perineal pouch. The pelvic diaphragm floor, providing a route of communication between the is formed by the levator ani and the coccygeus muscles gluteal region of the lower limb and the perineum.

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