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The inferior gluteal nerve (L5 kidney transplant and erectile dysfunction treatment himcolin 30 gm purchase,S1 erectile dysfunction systems order 30 gm himcolin,2)aarises from the roots of the Muscular branchesato plantaris impotence blood circulation order himcolin now, soleus erectile dysfunction causes in young males purchase himcolin online, gastrocnemius and the sciatic nerve and passes through the greater sciatic foramen below deep muscles at the back of the leg erectile dysfunction statistics age cheap himcolin online visa. In the gluteal region it penetrates and supplies gluteus Sural nerveaarises in the popliteal fossa and is joined by the sural maximus. It pierces the The posterior cutaneous nerve of the thigh (S1, 2, 3)apasses deep fascia in the calf and descends subcutaneously with the small through the greater sciatic foramen below piriformis. It passes behind the lateral malleolus and under the supply the skin of the scrotum, buttock and back of the thigh up to flexor retinaculum to divide into its cutaneous terminal branches the knee. It sends four motor branches and a cutaneous supply to the region by passing out of the greater sciatic foramen below pirifor- medial 3 /12 digits. It runs forwards in the pudendal plantar artery to the base of the 5th metatarsal where it divides into (Alcock’s) canal and gives off its inferior rectal branch in the superficial and deep branches. It continues its course to the perineum and the lateral 1 /12 digits and the remaining muscles of the sole. In the gluteal Branches: region it passes over the superior gemellus, obturator internus and in- Genicular branches to the knee joint. In addition it supplies the skin over the lateral lower two-thirds Muscular branchesato the hamstrings and the ischial part of of the leg and the whole of the dorsum of the foot except for the adductor magnus. Deep peroneal nerve (L4,5,S1,2)aruns with the anterior tibial Nerve to quadratus femoris (L4,5,S1)asupplies quadratus vessels over the interosseous membrane into the anterior compart- femoris and the inferior gemellus. The central and inferior parts of the acetabulum (a) Iliofemoral ligament (Bigelow’s ligament)ais inverted, Yshaped are devoid of articulating surface. It arises from the anterior inferior iliac spine and notch from which the ligamentum teres passes to the fovea on the inserts at either end of the trochanteric line. The capsule (c) Ischiofemoral ligamentafibres arise from the ischium and some attaches to the femur anteriorly at the trochanteric line and to the bases encircle laterally to attach to the base of the greater trochanter. Posteriorly the capsule attaches to the femur at a The majority of the fibres, however, spiral and blend with the higher levelaapproximately 1 cm above the trochanteric crest. This is an outpouching of synovial 2 Vessels in the ligamentum teres which enter the head through membrane through a defect in the anterior capsular wall under the small foramina in the fovea. The hip joint and gluteal region 103 Gluteus medius Gluteus medius Gluteus minimus Gluteus maximus Superior gluteal artery and nerve Inferior gluteal nerve Piriformis Obturator internus and gemelli Femoral insertion Inferior gluteal artery of gluteus maximus Quadratus femoris Posterior cutaneous nerve of thigh Internal pudendal nerve and artery Sciatic nerve Vastus lateralis Biceps femoris Adductor magnus Semimembranosus Opening in adductor magnus Semitendinosus Biceps (short head) Biceps (long head) Sciatic nerve Semimembranosus tendon Gastrocnemius Fig. Lateral rotation (0–45°): piriformis, obturators, the gemelli, Flexion (0–120°): iliacus and psoas predominantly. Medial rotation (0–45°): tensor fasciae latae, gluteus medius and Extension (0–20°): gluteus maximus and the hamstrings. Adduction (0–30°): adductor magnus, longus and brevis predomin- Circumduction: this is a combination of all movements utilizing all antly. Pertrochanteric Extracapsular The smaller diagram shows how the sacrotuberous and sacrospinous ligaments resist rotation of the sacrum Fig. Fractures near the head can cause avascular necrosis because of the disruption of the arterial supply to the head The fractured neck of femur (Fig. This occurs as the adductors, hamstrings and rectus femoris pull Nerves: of the gluteal region include the: sciatic nerve (L4,5,S1–3), upwards on the distal fragment whilst piriformis, the gemelli, obtur- posterior cutaneous nerve of the thigh, superior (L4,5,S1,2) and in- ators, gluteus maximus and gravity produce lateral rotation. The fold occurs as the overly- circumflex arteries, and the first perforating branch of the profunda, to ing skin is bound to the underlying deep fascia and not, as is often form the trochanteric and cruciate anastomoses, respectively. The greater and lesser The hip joint and gluteal region 105 47 The thigh Diaphragm Iliacus Right crus Femoral triangle Quadratus Tensor fasciae Inguinal ligament lumborum latae Psoas tendon Psoas major Pectineus Iliacus Adductor longus Inguinal ligament Rectus femoris Gracilis Pectineus Sartorius Adductor longus Vastus lateralis Vastus medialis Iliotibial tract Adductor magnus Opening in adductor magnus (for passage Patellar of femoral vessels retinacula Ligamentum patellae to popliteal fossa) Fig. Psoas, iliacus and the adductor The femoral triangle is outlined group of muscles The thigh is divided into flexor, extensor and adductor compartments. On the lateral side the fascia lata is condensed to form the iliotibial The membranous superficial fascia of the abdominal wall fuses to the tract (Fig. The tract is attached above to the iliac crest and fascia lata, the deep fascia of the lower limb, at the skin crease of the receives the insertions of tensor fasciae latae and three-quarters of glu- hip joint just below the inguinal ligament. The deep fascia of the thigh (fascia lata) The saphenous opening is a gap in the deep fascia which is filled with This layer of strong fascia covers the thigh. The lateral border of the inguinal ligament and bony margins of the pelvis and below to the tibial opening, the falciform margin, curves in front of the femoral vessels condyles, head of the fibula and patella. Three fascial septa pass from whereas on the medial side it curves behind to attach to the iliopectineal the deep surface of the fascia lata to insert onto the linea aspera of the line (Fig. The great saphenous vein pierces the cribriform fascia femur and consequently divide the thigh into three compartments. Superficial branches of the femoral artery and lymphatics are also transmitted through the saphenous opening. The saphenous opening is in the Contents of the subcutaneous tissue include: upper part of the triangle. The back of the thigh fuse and evaginate to form the femoral sheath below the inguinal liga- receives its sensory supply from the posterior cutaneous nerve of the ment. Superficial arteries: these include the four superficial branches of the femoral artery: the superficial circumflex iliac artery, superficial The contents of the anterior compartment of the thigh epigastric artery, superficial external pudendal artery and the deep (Fig. The boundaries of the femoral triangle are: the inguinal ligament Nerves: the femoral nerve (L2,3,4, p. The thigh 107 Iliac crest Fascia covering gluteus medius Tensor fasciae latae Gluteus maximus Iliotibial tract Rectus femoris Vastus lateralis Biceps femoris (long head) Fig. Note the two muscles inserted into the iliotibial tract The contents of the medial compartment of the thigh The adductor (subsartorial or Hunter’s) canal (Figs 47. It commences in the mid-portion of the thigh and is lateral rotator of the thigh at the hip) (see Muscle index, p. Nerves: the anterior and posterior divisions of the obturator nerve The roof: thickened fascia underlying sartorius. The contents of the adductor canal The contents of the posterior compartment of the thigh These include: the femoral artery, the femoral vein which lies deep to (Fig. They include: biceps femoris,semitendinosus,semimembranosus the lower limb with the great saphenous vein), the nerve to vastus medi- and the hamstring part of adductor magnus (see Muscle index, p. The muscles of the the intermediate cutaneous nerve of the thigh (branch of the femoral posterior compartment are supplied by the tibial component of the sci- nerve, p. The small diagrams show how the cruciate ligaments resist forward and backward displacement of the femur The knee joint (Figs 48. In the knee joint the femoral and tibial condyles attached above to the femoral epicondyle and below to the subcuta- articulate as does the patella and patellar surface of the femur. Unlike the medial collateral ligament is a large opening through which the synovial membrane is continuous it lies away from the capsule and meniscus. This bursa extends superiorly The collateral ligaments are taut in full extension and it is in this three fingerbreadths above the patella between the femur and quad- position that they are liable to injury when subjected to extreme val- riceps. Posteriorly the capsule communicates with another bursa under the Behind the knee the oblique popliteal ligament, a reflected exten- medial head of gastrocnemius and often, through it, with the bursa of sion from the semimembranosus tendon, strengthens the capsule (Fig. Anteriorly the capsule is reinforced by the ligamentum patellae mits the passage of the tendon of popliteus. The latter are reflected fibrous expansions Extracapsular ligaments: the capsule of the knee joint is reinforced arising from vastus lateralis and medialis muscles which blend with the by ligaments. Conversely, The anterior cruciate ligamentapasses from the front of the inter- the first stage of flexion is unlocking the joint by internal rotation of the condylar area of the tibia to the medial side of the lateral femoral medial tibial condyleaan action performed by popliteus. This ligament prevents hyperextension and resists for- The principal muscles acting on the knee are: ward movement of the tibia on the femur. The posterior cruciate ligamentapasses from the back of the inter- Flexion: predominantly the hamstrings but also gracilis, gastrocne- condylar area of the tibia to the lateral side of the medial condyle. The menisci (semilunar cartilages): these are crescentic fibrocarti- laginous ‘shock absorbers’ within the joint. The The femoral artery and vein pass through the hiatus in adductor magnus medial meniscus is C shaped and larger than the lateral meniscus. The lateral menis- the biceps tendon (superolateral) and semimembranosus reinforced cus is loosely attached to the tibia and connected to the femur by two by semitendinosus (superomedial). The classic medial meniscus injury occurs when a footballer The roof consists of: deep fascia which is penetrated at an inconstant twists the knee during running. It is a combination of external rotation position by the small saphenous vein as it drains into the popliteal vein. The floor consists of (from above downwards): the posterior lower Blood supply: is from the rich anastomosis formed by the genicular femur, the posterior surface of the knee joint and popliteus. The contents of the fossa include (from deep to superficial): the Nerve supply: is from branches of the femoral, tibial, common per- popliteal artery, vein and tibial nerve. Knee movements The popliteal pulse is notoriously difficult to feel because the artery Flexion and extension are the principal movements at the knee. Whenever a popliteal pulse is easily pal- rotation is possible when the knee is flexed but is lost in extension. The knee joint and popliteal fossa 111 49 The leg Rectus femoris Vastus lateralis Vastus Vastus lateralis Biceps femoris medialis Iliotibial tract Ligamentum patellae Sartorius Peroneus longus Peroneus longus Soleus Gastrocnemius and brevis Gastrocnemius and soleus Extensor digitorum Tibialis longus anterior Extensor hallucis longus Peroneus brevis Subcutaneous surface of tibia Peroneus retinaculum Superior and inferior extensor retinacula Peroneus tertius Extensor digitorum brevis Peroneus tertius Fig. Students are often confused about the description of movements The superior extensor retinaculum: is a transverse band attached to of the foot. Extension of the foot (dorsiflexion) refers to lifting the the anterior borders of the tibia and fibula. The deep fascia of the leg The deep fascia of the leg is continuous above with the deep fascia of The peroneal compartment of the leg (Figs 49. It envelops the leg and fuses with the periosteum of the tibia This compartment consists of two musclesaperoneus longus and at the anterior and medial borders. The contents osseous membrane, divide the leg into four compartments: extensor, of the peroneal compartment include: peroneal, superficial and deep flexor. The inferior per- These are, respectively, synovial and fibrous joints between the tibia oneal retinaculum is a similar band of fascia which is continuous with and fibula at their proximal and distal ends. The The flexor muscles of the calf are considered in two groupsasuperficial fibres of the membrane run obliquely downwards from tibia to fibula. All flexor muscles of the calf receive their Its function is to bind together the bones of the leg as well as providing nerve and arterial supplies from the tibial nerve and the posterior tibial a surface for muscle attachment. The contents of the flexor compartment of the calf include: The extensor aspects of the leg and dorsum of the foot Superficial flexor muscle group: gastrocnemius, soleus and plan- (Figs 49. Note that all of these muscles The extensor group consists of four muscles in the leg (see below) and are inserted into the middle third of the posterior surface of the cal- extensor digitorum brevis in the foot. A small bursa (the The contents of the extensor compartment of the leg are as follows: retrocalcaneal bursa) occupies the space between the upper third of the Muscles: tibialis anterior, extensor hallucis longus, extensor digito- posterior surface of the calcaneus and the Achilles tendon. Within rum longus and peroneus tertius (unimportant in function) (see Muscle soleus, and to a lesser extent gastrocnemius, there is an extensive index, p. Midtarsal (calcaneocuboid) ligament Talus talocalcaneal Sustentaculum tali Tibialis ligament posterior Facet for medial malleolus Calcaneofibular Head of talus Flexor ligament Navicular digitorum Peroneus brevis Tuberosity of navicular longus Peroneus longus Medial cuneiform Flexor 1 2 hallucis longus First metatarsal 3 Fig. Posterior The major joints are shown tibiofibular Anterior tibiofibular ligament ligament Posterior Talus talofibular Navicular Tendo Deltoid ligament calcaneus ligament Position Medial of bursa cuneiform First metatarsal Bifurcate ligament Cuboid Cervical ligament Long plantar ligament Calcaneofibular ligament Fig. The articular surfaces are covered with cartilage and synovial the tendocalcaneus by a bursa (retrocalcaneal bursa) (Fig. The capsule is Medial and lateral tubercles are present on the inferior surface to which reinforced on either side by strong collateral ligaments but is lax anter- the plantar aponeurosis is attached. The peroneal tubercle, a small projection on the lateral sur- deep component which is a vertical band passing from the medial face of the calcaneus, separates the tendons of peroneus longus and malleolus to the talus. Navicular: has facets for the articulations with the head of the talus The lateral collateral ligament consists of three bands: the anterior posteriorly and the three cuneiforms anteriorly. It has a tuberosity on its and posterior talofibular ligaments and the calcaneofibular ligament medial aspect which provides attachment for tibialis posterior. Abduction/adduction forces on the ankle can cause a Cuneiforms: there are three cuneiforms which articulate anteriorly sprainaan incomplete tear of one of the collateral ligaments. Their wedge- tears of the ligaments also occur and lead to painful instability at the shape helps to maintain the transverse arch of the foot. Severe forces on the ankle joint can Metatarsals and phalanges: these are similar to the metacarpals and result in fracture or fracture dislocation. The movements at the ankle The head is grooved on its inferior surface for the two sesamoid bones It is important to note that the inversion and eversion movements of within the tendon of flexor hallucis brevis. Inversion and eversion Dorsiflexion: tibialis anterior and to a lesser extent extensor hallucis movements occur at the subtalar joint. The talcocalcaneal jointais a synovial plane joint formed by the Plantarflexion: gastrocnemius and soleus and to a lesser extent articulation of the upper surface of the calcaneus with the lower tibialis posterior, flexor hallucis longus and flexor digitorum longus. This joint is com- faces for articulation with the tibia, medial malleolus and lateral malle- posed of the calcaneocuboid joint and the talonavicular component of olus, respectively. To the groove’s lateral The calcaneocuboid jointais a synovial plane joint formed side is the posterior (lateral) tubercle, sometimes known as the os between the anterior surface of the calcaneus and the posterior trigonum, as it ossifies from a separate centre to the talus. Other from the sustentaculum tali to the tuberosity of the navicular forming a muscles insert on the dorsum of the foot but arise from the leg. It reinforces the digitorum longus is joined on its lateral side by a tendon from extensor capsule of the talocalcaneonavicular joint. Arterial supply: is from the dorsalis pedis arteryathe continuation Short plantar ligament: runs from the undersurface of the calca- of the anterior tibial artery. Medial and lateral (talocalcaneal) ligaments: strengthen the Nerve supply: is from the deep peroneal nerve via its medial and lat- capsule of the talocalcaneal joint. The latter supplies extensor digitorum brevis Interosseous talocalcaneal ligament: runs in the sinus tarsi, a whereas the former receives cutaneous branches from the skin. Deep transverse metacarpal ligaments: join the plantar ligaments The sole of the foot of the metatarsophalangeal joints of the five toes. The skin of the sole is supplied by the medial and lateral plantar The arches of the foot branches of the tibial nerve. The medial calcaneal branch of the tibial The integrity of the foot is maintained by two longitudinal (medial and nerve innervates a small area on the medial aspect of the heel. The arches are held together by a combination of bony, ligamentous and muscular factors The plantar aponeurosis so that standing weight is taken on the posterior part of the calcaneum This aponeurosis lies deep to the superficial fascia of the sole and and the metatarsal heads as a result of the integrity of the arches. The arch is bound together by the spring ligament, muscles split into two parts which pass on either side of the flexor tendons and and supported from above by tibialis anterior and posterior. The arch is bound together by The muscular layers of the sole the long and short plantar ligaments and supported from above by per- 1st layer consists of: abductor hallucis, flexor digitorum brevis and oneus longus and brevis. Transverse arch: comprises the cuneiforms and bases of the meta- 2nd layer consists of: flexor digitorum accessorius, the lumbricals tarsals.

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Trough phenobarbital serum concentrations should be measured after steady state is attained in 3–5 half-lives impotence kidney stones cheap himcolin 30 gm buy on-line. Since the patient is expected to have a phenobarbital half-life equal to 60 hours impotence effects on marriage discount himcolin 30 gm buy on line, the steady-state concentrations could be obtained any time after 2 weeks of dosing (5 phenobarbital half-lives = 5 ⋅ 60 h = 300 h or 13 d) erectile dysfunction diagnosis code himcolin 30 gm amex. Phe- nobarbital serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy what causes erectile dysfunction yahoo best 30 gm himcolin, or if the patient develops potential signs or symp- toms of phenobarbital toxicity impotence drugs over counter himcolin 30 gm order with amex. Using linear pharmacokinetics, the resulting steady-state phenobarbital serum con- centration would equal Dnew = (Cssnew/Cssold) Dold = (15 μg/mL / 8. A steady-state trough phenobarbital serum concentration should be measured after steady state is attained in 2 weeks. Phenobarbital serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of phenobarbital toxicity. Phenobarbital clearance can be computed using a steady-state phenobarbital concen- tration: Cl = [F(D/τ)] / Css = [1(30 mg/12 h)] / (8. Phenobarbital serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of phenobarbital toxicity. Estimate clearance and volume of distribution according to disease states and conditions present in the patient. Once the correct clearance and volume of distribution estimates are identified for the patient, they can be converted into the primidone half-life (t1/2) and elimination rate constant (k) estimates using the following equations: t1/2 = (0. To avoid side effects, the starting dose would be 50% of this anticipated maintenance dose (125 mg every 12 hours) and would be titrated to the full dose over 1–2 weeks. Steady-state trough primidone and phenobarbital serum concentrations should be measured after steady state for both agents is attained in 3–5 half-lives. Since the patient is expected to have a phenobarbital half-life equal to 100 hours or more, the steady-state concentrations could be obtained any time after 3–4 weeks of dosing at the full primidone maintenance dose (5 phenobarbital half-lives = 5 ⋅ 100 h = 500 h or 21 d). Primidone and phenobarbital serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of primidone toxicity. To avoid side effects, the starting dose would be 50% of this anticipated maintenance dose (125 mg every 6 hours) and would be titrated to the full dose over 1–2 weeks according to response and adverse effects. Steady-state trough primidone and phenobarbital serum concentrations should be measured after steady state for both agents is attained in 3–5 half-lives. Since the patient is expected to have a phenobarbital half-life equal to 100 hours or more, the steady-state concentrations could be obtained any time after a 3–4 weeks of dosing at the full primidone maintenance dose (5 phenobarbital half-lives = 5 ⋅ 100 h = 500 h or 21 d). Primidone and phenobarbital serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of primidone toxicity. Using linear pharmacokinetics, the primidone dose necessary to cause the change in steady-state concentration would equal Dnew = (Cssnew/Cssold) Dold = (6 μg/mL / 4. The dosage regimen would be titrated to this value over a period of 1–2 weeks to avoid adverse effects. Using linear pharmacokinetics, the resulting steady-state phe- nobarbital serum concentration would equal Css,new = (Dnew/Dold) Css,old = (1500 mg/d / 1000 mg/d) 11. A steady-state trough primidone and phenobarbital serum concentration should be measured after steady state is attained in 3–4 weeks. Primidone and phenobarbital serum concentrations should also be measured if the patient experiences an exacerba- tion of their epilepsy, or if the patient develops potential signs or symptoms of primi- done toxicity. The patient would be expected to achieve steady-state conditions for both primi- done and phenobarbital after 3–4 weeks of therapy. Primidone clearance can be computed using a steady-state primidone concentra- tion: Cl = [F(D/τ)] / Css = [1(500 mg/12 h)] / (4. Using linear pharma- cokinetics, the resulting steady-state phenobarbital serum concentration would equal Css,new = (Dnew/Dold) Css,old = (1500 mg/d / 1000 mg/d) 11. Primidone and phenobarbital serum concentrations should also be measured if the patient experiences an exacerba- tion of their epilepsy, or if the patient develops potential signs or symptoms of primi- done toxicity. Estimate clearance and volume of distribution according to disease states and conditions present in the patient. Once the correct clearance and volume of distribution estimates are identified for the patient, they can be converted into the primidone half-life (t1/2) and elimination rate constant (k) estimates using the following equations: t1/2 = (0. To avoid side effects, the starting dose would be 50% of this antici- pated maintenance dose (50 mg every 6 hours) and would be titrated to the full dose over 1–2 weeks. Steady-state trough primidone and phenobarbital serum concentrations should be measured after steady state for both agents is attained in 3–5 half-lives. Since the patient is expected to have a phenobarbital half-life equal to 60 hours or more, the steady-state concentrations could be obtained any time after 2 weeks of dosing at the full primidone maintenance dose (5 phenobarbital half-lives = 5 ⋅ 60 h = 300 h or 13 d). Primidone and phenobarbital serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of primidone toxicity. The suggested initial mainte- nance dosage rate for primidone in a pediatric patient is 12–23 mg/kg/d. To avoid side effects, the starting dose would be 50% of this anticipated maintenance dose (50 mg every 8 hours) and would be titrated to the full dose over 1–2 weeks according to response and adverse effects. Steady-state trough primidone and phenobarbital serum concentrations should be measured after steady state for both agents is attained in 3–5 half-lives. Since the patient is expected to have a phenobarbital half-life equal to 60 hours or more, the steady- state concentrations could be obtained any time after 2 weeks of dosing at the full primidone maintenance dose (5 phenobarbital half-lives = 5 ⋅ 60 h = 300 h or 13 d). Primidone and phenobarbital serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops poten- tial signs or symptoms of primidone toxicity. Using linear pharmacokinetics, the primidone dose necessary to cause the change in steady-state concentration would equal Dnew = (Cssnew/Cssold) Dold = (8 μg/mL / 5. The dosage regimen would be titrated to this value over a period of 1–2 weeks to avoid adverse effects. Using linear pharmacokinetics, the resulting steady-state phe- nobarbital serum concentration would equal Css,new = (Dnew/Dold) Css,old = (300 mg/d / 225 mg/d) 18 μg/mL = 24 μg/mL. A steady-state trough primidone and phenobarbital serum concentration should be measured after steady state is attained in 2 weeks. Primidone and phenobarbital serum concentrations should also be measured if the patient experiences an exacerba- tion of their epilepsy, or if the patient develops potential signs or symptoms of primi- done toxicity. The patient would be expected to achieve steady-state conditions for both primi- done and phenobarbital after 2 weeks of therapy. Primidone clearance can be computed using a steady-state primidone concentra- tion: Cl = [F(D/τ)] / Css = [1(75 mg/8 h)] / (5. Steady-state trough primidone and phenobarbital serum concentrations should be measured after steady state is attained in 2 weeks. Primidone and phenobarbital serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of primidone toxicity. Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program. The pharmacokinetic parameters computed by the program are a volume of distri- bution of 36 L, a half-life equal to 217 hours, and a clearance equal to 0. The one-compartment model first-order absorption equations used by the program to compute doses indicates that a dose of 60 mg every 24 hours will produce a steady-state phenobarbital concentration of 21 μg/mL. Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program. The pharmacokinetic parameters computed by the program are a volume of distri- bution of 44 L, a half-life equal to 97 hours, and a clearance equal to 0. The one-compartment model first-order absorption equations used by the program to compute doses indicates that a dose of 240 mg every 24 hours will produce a steady-state phenobarbital concentration of 29 μg/mL. Phenylethylmalonamide serum levels in patients treated with primidone and the effects of other antiepileptic drugs. Update on drug sieving coefficients and dosing adjustments during continuous renal replacement therapies. While the exact mechanism of action is not known, the antiepileptic effect of ethosuximide is thought to result from its ability to decrease low-threshold calcium currents in thalamic neurons. Generally, administration of smaller doses and more frequent dosing of the drug produce relief from these side effects. In the upper end of the therapeutic range (>70 μg/mL) some patients will begin to experience the concentration-dependent adverse effects of ethosux- imide treatment: drowsiness, fatigue, lethargy, dizziness, ataxia, hiccups, euphoria, and headaches. Idiosyncratic side effects that are independent of concentration include rash, systemic lupus-like syndromes, and blood dyscrasias (leukopenia, pancytopenia). Simple partial seizures Drugs of choice locally) (without impaired Carbamazepine consciousness) Phenytoin a. Absence seizures (typical or Drugs of choice or nonconvulsive) atypical; also known as petit Ethosuximide mal seizures) Valproic acid Alternatives Lamotrigine Clonazepam Zonisamide Levetiracetam 2. While it is desirable to entirely abolish all seizure episodes, it may not be possible to accomplish this in many patients. Patients should be monitored for concentration-related side effects (drowsiness, fatigue, lethargy, dizziness, ataxia, hiccups, euphoria, headaches) as well as gastrointestinal upset associated with local irritation of gastric mucosa (gastric distress, nausea, vomiting, anorexia). Serious, but rare, idiosyncratic side effects include systemic lupus-like syn- dromes, leukopenia, and pancytopenia. Because epilepsy is an episodic disease state, patients do not experience seizures on a continuous basis. Thus, during dosage titration it is difficult to tell if the patient is responding to drug therapy or simply is not experiencing any abnormal central nervous system discharges at that time. Patients are more likely to accept drug therapy if adverse reactions are held to the absolute minimum. At concentrations exceeding 100 μg/mL, the drug may follow nonlinear pharmacokinetics, presumably owing to Michaelis-Menten (concentration dependent or saturable) metabolism. However, based on animal studies, ethosuximide oral bioavailability of capsules (250 mg) and syrup (250 mg/5 mL) is assumed to be 100%. Because of this, patients with liver cirrhosis or acute hepatitis may have reduced ethosuximide clearance because of destruction of liver parenchyma. This loss of functional hepatic cells reduces the amount of enzymes avail- able to metabolize the drug and decreases clearance. An index of liver dysfunction can be gained by applying the Child-Pugh clinical classification system to the patient (Table 14-2). Each of these areas is given a score of 1 (normal) to 3 (severely abnormal; Table 14-2), and the scores for the five areas are summed. The Child-Pugh score for a patient with normal liver func- tion is 5 while the score for a patient with grossly abnormal serum albumin, total biliru- bin, and prothrombin time values in addition to severe ascites and hepatic encephalopathy is 15. A Child-Pugh score greater than 8 is grounds for a decrease of 25–50% in the initial daily drug dose for ethosuximide. As in any patient with or without liver dysfunction, ini- tial doses are meant as starting points for dosage titration based on patient response and avoidance of adverse effects. Ethosuximide serum concentrations and the presence of adverse drug effects should be monitored frequently in patients with liver cirrhosis. Similarly, a small amount (20–30%) of ethosuximide is usually eliminated unchanged by the kidneys so patients with renal dysfunction (creatinine clearance <30 mL/min) receiving ethosuximide should be closely monitored. It allows individualized target serum concen- trations to be chosen for a patient, and each pharmacokinetic parameter can be customized to reflect specific disease states and conditions present in the patient. Doses are based on those that commonly produce steady-state concentrations in the lower end of the therapeutic range, although there is a wide variation in the actual concentrations for a specific patient. Pharmacokinetic Dosing Method The goal of initial dosing of ethosuximide is to compute the best dose possible for the patient given their set of disease states and conditions that influence ethosuximide phar- macokinetics and the epileptic disorder being treated. In order to do this, pharmacokinetic parameters for the patient will be estimated using average parameters measured in other patients with similar disease state and condition profiles. Unfortunately, there is no good way to estimate the elimination characteristics of liver metabolized drugs using an endogenous marker of liver function in the same manner that serum creatinine and esti- mated creatinine clearance are used to estimate the elimination of agents that are renally eliminated. Because of this, a patient is categorized according to the disease states and conditions that are known to change ethosuximide clearance, and the clearance previ- ously measured in these studies is used as an estimate of the current patient’s clearance. For example, for a 20-kg pediatric patient, ethosuximide clearance would be assumed to equal 16 mL/h/kg: 20 kg ⋅ 16 mL/h/kg = 320 mL/h or 0. To produce the most con- servative ethosuximide doses in patients with multiple concurrent disease states or condi- tions that affect ethosuximide pharmacokinetics, the disease state or condition with the smallest clearance should be used to compute doses. Thus, for a 20-kg pediatric patient, the estimated ethosuximide volume of distribu- tion would be 14 L: V = 0. When oral therapy is required, ethosuximide has good bioavailability (F = 1), and once or twice dosing pro- vides a relatively smooth serum concentration/time curve that emulates an intravenous infusion. Because of this, a very simple pharmacokinetic equation that computes the aver- age ethosuximide steady-state serum concentration (Css in μg/mL = mg/L) is widely used and allows maintenance dosage calculation: Css = [F(D/τ)] / Cl or D = (Css ⋅ Cl ⋅τ) / F, where F is the bioavailability fraction for the oral dosage form (F = 1 for oral ethosux- imide products), D is the dose of ethosuximide in milligrams, Cl is ethosuximide clear- ance in liters per hour, and τ is the dosage interval in hours. Suggest an initial ethosuximide dosage regimen designed to achieve a steady-state ethosuximide concentration equal to 50 μg/mL. Estimate clearance and volume of distribution according to disease states and con- ditions present in the patient. Once the correct clearance and volume of distribution estimates are identified for the patient, they can be converted into the ethosuximide half-life (t1/2) and elimination rate constant (k) estimates using the following equations: t1/2 = (0. A steady-state trough ethosuximide serum concentration should be measured after steady state is attained in 3–5 half-lives. Since the patient is expected to have a half-life equal to 41 hours, the ethosuximide steady-state concentration could be obtained any time after the ninth day of dosing (5 half-lives = 5 ⋅ 41 h = 205 h or 9 d). Ethosuximide serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of ethosuximide toxicity. Suggest an initial ethosuximide dosage regimen designed to achieve a steady-state ethosuximide concentra- tion equal to 50 μg/mL. Estimate clearance and volume of distribution according to disease states and con- ditions present in the patient. Once the correct clearance and volume of distribution estimates are identified for the patient, they can be converted into the ethosuximide half-life (t1/2) and elimination rate constant (k) estimates using the following equations: t1/2 = (0. A steady-state trough ethosuximide serum concentration should be measured after steady state is attained in 3–5 half-lives. Since the patient is expected to have a half-life equal to 30 hours, the ethosuximide steady-state concentration could be obtained any time after the sixth day of dosing (5 half-lives = 5 ⋅ 30 h = 150 h or 6 d). Ethosuximide serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of ethosuximide toxicity. Literature-Based Recommended Dosing Because of the large amount of variability in ethosuximide pharmacokinetics, even when concurrent disease states and conditions are identified, most clinicians believe that the use of standard ethosuximide doses for various situations are warranted.

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However erectile dysfunction doctors huntsville al purchase himcolin 30 gm with visa, most drugs used in labor and the bulk flow of cerebrospinal fluid carried through the delivery are not highly ionized and will cross erectile dysfunction treatment by ayurveda order himcolin american express. Some drugs erectile dysfunction treatment south africa order himcolin 30 gm without a prescription, such as penicillin erectile dysfunction protocol book download buy himcolin with a visa, 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 erectile dysfunction self test order cheap himcolin, since but will be actively transported by the choroid plexus out the pH of fetal blood is around 7. Penicillin, The existence of a barrier between the blood and testes for example, is a less effective antibiotic centrally than it is indicated by the absence of staining in testicular tissue is peripherally. Morphological studies indicate that the barrier lies beyond the capillary endothelial cells and is most likely to be found at the Placental Barrier specialized Sertoli–Sertoli cell junction. It appears that The blood vessels of the fetus and mother are separated Pgp, the efflux transporter protein, also plays a role in by a number of tissue layers that collectively constitute forming this blood-testis barrier. Drugs that traverse this barrier plays a role in preventing certain chemotherapeutic will reach the fetal circulation. The placental barrier, agents from reaching specific areas of the testis and thus like the blood-brain barrier, does not prevent transport hinders treatment of the neoplasm. Alterations in gastric reduce the amount of foreign chemicals, such as motility may affect the amount of time a drug drugs, that enter the body. One of the more promi- spends in the region of the gastrointestinal tract, nent of these mechanisms is an efflux transport sys- where it undergoes the most extensive absorption. Finally, system is: changes in drug formulation can alter absorption by (A) Facilitated diffusion changing dissolution rates. P-glycoprotein transporters in the intestinal lu- (C) Cytochrome P450 3A men serve as an efflux transporter for many drugs. All of the following statements concerning the into which they were absorbed and back into the in- blood-brain barrier and the passage of drugs from testinal lumen, reducing absorption. Un-ionized drugs cross into the cerebrospinal likelihood that drugs will cross the blood-brain bar- fluid more readily than ionized drugs. Lead can substitute for calcium in the bone crys- (D) P glycoprotein serves to pump drugs back into tal lattice, resulting in bone brittleness. Bone may the systemic circulation from endothelial cells lining become a reservoir for other substances as well. Drugs with extremely high lipid– tial site for drug accumulation of lead that has been water partition coefficients tend to accumulate in fat, ingested? The primary site of absorption is the small intes- Multidrug transporters in prokaryotic and eukary- tine. Because of its large surface area and high otic cells: physiological functions and transport blood perfusion rate, the small intestine is optimal mechanisms. The as the primary cause for the low amounts of orally physician also prescribed diltiazem, a calcium administered cyclosporine reaching the systemic channel blocker used for the treatment of circulation. Since he did not have hypertension, increases the bioavailability of cyclosporine, the patient wondered why this additional drug was reducing the dose of drug needed. Though an the development of hypertension, and the diltiazem oral formulation is available, it has low somewhat protects the patient from this adverse bioavailability (very little reaches the systemic effect. Drug metabolism the primary phase I enzyme system involved in the ox- changes the chemical structure of a drug to produce a idative metabolism of drugs and other chemicals. These drug metabolite, which is frequently but not universally enzymes also are responsible for all or part of the me- less pharmacologically active. Metabolism also renders tabolism and synthesis of a number of endogenous com- the drug compound more water soluble and therefore pounds, such as steroid hormones and prostaglandins. Enzymes within examples of compounds for which each isoform plays a these categories exhibit some limited specificity in rela- substantial role in their metabolism, are listed in Table 4. For example, the calcium specific hydrolytic enzymes, such as esterases and ami- channel blocking drug verapamil is primarily metabolized dases, have not received much research attention. However, as dis- isoform involved in human drug metabolism, both in cussed later, there is still a great deal of substrate speci- terms of the amount of enzyme in the liver and the vari- ficity within a given enzyme family. It is becoming increasingly clear that dif- ferent enzyme expression patterns, and thus different drug metabolism capabilities, are observed throughout This isoform may account for more than 50% of all the various stages of life. In fact, it is believed that drugs as substrates, its relative abundance in the liver is two drugs (substrates) can occupy the active site simul- quite low. Any change Involved in Human Drug in the metabolism of these two drugs, either increased Metabolism or decreased, can have profound adverse effects. Enzyme Inhibition hibitor) is itself metabolized by the enzyme to form a reactive species that binds irreversibly to the enzyme Enzyme inhibition is the most frequently observed re- and prevents any further metabolism by the enzyme. The most the enzyme molecule and thus can be overcome only by common type of inhibition is simple competitive inhibi- the proteolytic degradation of that particular enzyme tion, wherein two drugs are vying for the same active molecule and subsequent synthesis of new enzyme pro- site and the drug with the highest affinity for the site tein. Whereas decreased to such a degree that the patient is exposed one frequently associates enzyme inhibition with an in- to 17 times as much of parent triazolam as when keto- crease in potential for toxicity, enzyme induction is most conazole is not present. Both time required for synthesis of Depending on the isoform, these enzymes have varying new enzyme protein (transcription and translation) and reactivity toward a number of pharmacologically active the half-life of the inducing drug affect the time course compounds, such as opioids, androgens, estrogens, of induction. Little taching (conjugating) a more polar molecule to the overlap in substrate specificities of the two isoforms original drug molecule to increase water solubility, appears to exist. A representative tabolism of a number of drugs, neurotransmitters, reaction of this type is shown in Figure 4. Like the afore- etary supplement for the treatment of various condi- mentioned enzymes, sulfate conjugation typically ren- tions. Likelihood of adverse topurine so that the dose may be adjusted downward if events, such as the dyskinesias associated with certain they are found to be deficient in this enzyme. Though most drug metabolism enzymes reside in the Recently, variant alleles (and thus polymorphisms) liver, other organs may also play an important role. As leaves its site of action, it may remain in the body for a early as the late 1950s it was recognized that individuals considerable period, especially if it is strongly bound to might differ in whether they could acetylate certain tissue components. In this case, activity and drug elimination are to be seen as related the individuals studied appeared to segregate into two but separate phenomena. Excretion, along with metabolism and tissue redis- It was later discovered that this polymorphism ex- tribution, is important in determining both the duration isted in the N-acetyltransferase-2 gene and thus the of drug action and the rate of drug elimination. More important, it has become clear Excretion is a process whereby drugs are transferred that slow acetylators (about 50% of the caucasian popu- from the internal to the external environment, and the lation) are more prone to adverse effects following ad- principal organs involved in this activity are the kid- ministration of certain drugs than fast acetylators. As the ultrafiltrate is formed, Glomerular Filtration any drug that is free in the plasma water, that is, not The ultrastructure of the glomerular capillary wall is bound to plasma proteins or the formed elements in the such that it permits a high degree of fluid filtration while blood (e. This selective filtration is im- All unbound drugs will be filtered as long as their mo- portant in that it prevents the filtration of plasma pro- lecular size, charge, and shape are not excessively large. The greater restriction to filtration of back-diffusion occurs primarily in the distal tubules and charged molecules, particularly anions, is probably collecting ducts, where most of the urine acidification due to an electrostatic interaction between the filtered takes place. Since it is the un-ionized form of the drug molecule and the fixed negative charges within the that diffuses from the tubular fluid across the tubular glomerular capillary wall. These highly anionic struc- cells into the blood, it follows that acidification in- tural components of the wall contribute to an electro- creases reabsorption (or decreases elimination) of weak static barrier and are most likely in the endothelial or acids, such as salicylates, and decreases reabsorption (or glomerular basement membrane regions. Differences in the not have sufficient lipid solubility, urinary pH changes three-dimensional shape of macromolecules result in a will have little influence on urinary drug excretion. For example, one can enhance the cient retention of proteins within the circulation is at- elimination of a barbiturate (a weak acid) by adminis- tributed to a combination of factors, including their tering bicarbonate to the patient. This procedure alka- globular structure, their large molecular size, and the linizes the urine and thus promotes the excretion of the magnitude of their negative charge. For through the use of an acidifying salt, such as ammonium instance, inflammation of the glomerular capillaries chloride. Anything that alters drug–protein A number of drugs can serve as substrates for the two binding, however, will change the drug filtration rate. The usual range of half-lives seen for most drugs that These transport systems, which actively transfer drugs are cleared solely by glomerular filtration is 1 to 4 hours. One drug substrate can Also, since water constitutes a larger percentage of compete for transport with a simultaneously adminis- the total body weight of the newborn than of individu- tered or endogenous similarly charged compound; this als in other age groups, the apparent volume of distri- competition will decrease the overall rate of excretion bution of water-soluble drugs is greater in neonates. The secretory capacity of both the or- This results in a lower concentration of drug in the ganic anion and organic cation secretory systems can be blood coming to the kidneys per unit of time and hence saturated at high drug concentrations. In general, the movement of drugs is favored from the tubular lumen to blood, partly because of the reabsorption of water that occurs throughout most portions of the nephron, which results in an increased concentration of drug in the luminal Active transport fluid. Hence, a reduction in se- lar secretion may be metabolized to compounds that cretory activity does not reduce the excretory process to are. This is often true for metabolites that are formed as zero but rather to a level that approximates the a result of conjugative reactions. Some substances filtered at the glomerulus are reab- These active secretory systems are important in sorbed by active transport systems found primarily in drug excretion because charged anions and cations are the proximal tubules. Active reabsorption is particularly often strongly bound to plasma proteins and therefore important for endogenous substances, such as ions, are not readily available for excretion by filtration. The the active secretory systems can rapidly and efficiently probable location of the active transport system is on remove many protein-bound drugs from the blood and the luminal side of the proximal cell membrane. Bidirectional active transport across the proximal Any drug known to be largely excreted by the kid- tubule also occurs for some compounds; that is, a drug ney that has a body half-life of less than 2 hours is prob- may be both actively reabsorbed and secreted. Several pharmacologically active urate is probably reabsorbed, whereas that eventually drugs, both anions and cations, known to be secreted are found in the urine is mostly derived from active tubular listed in Table 4. It is important to appreciate that these tubular Most drugs act by reducing active transport rather transport mechanisms are not as well developed in the than by enhancing it. In addition, their functional ca- loss (uricosuric agents, such as probenecid and sulfin- pacity may be diminished in the elderly. Thus, com- pyrazone) probably inhibit active urate reabsorption, pounds normally eliminated by tubular secretion will be while pyrazinamide, which reduces urate excretion, may excreted more slowly in the very young and in the older block the active tubular secretion of uric acid. This age dependence of the rate of renal drug se- plicating observation is that a drug may primarily in- cretion may have important therapeutic implications hibit active reabsorption at one dose and active secre- and must be considered by the physician who prescribes tion at another, frequently lower, dose. The transport Prostaglandins Neostigmine mechanism is in the luminal portion of the membrane of the Salicylate Quinine proximal tubular cell. This is drugs pass through the hepatocyte membrane by diffu- offered as an explanation for the apparently paradoxi- sion. The subsequent passage of substances into the bile, cal effects of low and high doses of drugs on the total however, is much more selective. Compounds of group A are those whose concentration in bile and plasma are almost identical (bile–plasma ra- tio of 1). Group B contains the bile salts, bilirubin The rate of urinary drug excretion will depend on the glucuronide, sulfobromophthalein, procainamide, and drug’s volume of distribution, its degree of protein bind- others, whose ratio of bile to blood is much greater than ing, and the following renal factors: 1, usually 10 to 1,000. Extent of active tubular secretion of the com- However, biliary excretion plays a major role (5–95% of pound the administered dose) in drug removal for some an- 5. Possibly, extent of active tubular reabsorption ions, cations, and certain un-ionized molecules, such as cardiac glycosides. In addition, biliary elimination may Changes in any of these factors may result in clini- be important for the excretion of some heavy metals. In the final Cardiac glycosides, anions, and cations are trans- analysis, the amount of drug that finally appears in the ported from the liver into the bile by three distinct and urine will represent a balance of filtered, reabsorbed independent carrier-mediated active transport systems, (passively and actively), and secreted drug. For many the last two closely resembling those in the renal proxi- drugs, the duration and intensity of pharmacological ef- mal tubules that secrete anions and cations into tubular fect will be influenced by the status of renal function, urine. As is true for renal tubular secretion, protein- because of the major role played by the kidneys in drug bound drug is completely available for biliary active and metabolite elimination. Thus, the ability cleared by the kidney, and the potential for drug toxic- of certain compounds to be actively secreted into bile ity, especially if renal function is reduced. On the other hand, most drugs that are secreted by Biliary Excretion the liver into the bile and then into the small intestine The liver secretes about 1 L of bile daily. The physicochem- composition depend on the secretory activity of the he- ical properties of most drugs are sufficiently favorable patic cells that line the biliary canaliculi. As the bile for passive intestinal absorption that the compound will flows through the biliary system of ducts, its composi- reenter the blood that perfuses the intestine and again tion can be modified in the ductules and ducts by the be carried to the liver. Such recycling may continue (en- processes of reabsorption and secretion, especially of terohepatic cycle or circulation) until the drug either un- electrolytes and water. For example, osmotically active dergoes metabolic changes in the liver, is excreted by compounds, including bile acids, transported into the the kidneys, or both. This process permits the conserva- bile promote the passive movement of fluid into the tion of such important endogenous substances as the duct lumen. In the gallbladder, composition of the bile bile acids, vitamins D3 and B12, folic acid, and estrogens is modified further through reabsorptive processes. The passage of most foreign compounds from the Extensive enterohepatic cycling may be partly re- blood into the liver normally is not restricted because sponsible for a drug’s long persistence in the body. Hence, drugs with molecular change resins have been used clinically to interrupt en- weights lower than those of most protein molecules terohepatic cycling and trap drugs in the gastrointesti- readily reach the hepatic extracellular fluid from the nal tract. A number of compounds are taken up into the As stated earlier, many foreign compounds are ei- liver by carrier-mediated systems, while more lipophilic ther partially or extensively metabolized in the liver. Finally, the administration of one drug may influ- Adriamycin Methadone ence the rate of biliary excretion of a second coadmin- istered compound. These effects may be brought about Amphetamine Metronidazole Chlordecone Morphine through an alteration in one or more of the following 1,25-Dihydroxyvitamin D3 Phenytoin factors: hepatic blood flow, uptake into hepatocytes, rate Estradiol Polar Glucuronic Acid of biotransformation, transport into bile, or rate of bile Conjugates formation. In addition, antibiotics may alter the intes- Indomethacin Polar Sulfate Conjugates tinal flora in such a manner as to diminish the presence Mestranol Sulindac of sulfatase and glucuronidase-containing bacteria. This would result in a persistence of the conjugated form of the drug and hence a decrease in its enterohepatic re- circulation. Conjugation of a compound or its metabolites is espe- cially important in determining whether the drug will undergo biliary excretion. Conjugation generally en- Any volatile material, irrespective of its route of ad- hances biliary excretion, since it both introduces a ministration, has the potential for pulmonary excretion. Molecular weight the body primarily through the respiratory tract can be may, however, be less important in the biliary excretion expected to be excreted by this route. Conjugated drugs will not be reab- transport systems are involved in the loss of substances in sorbed readily from the gastrointestinal tract unless expired air; simple diffusion across cell membranes is the conjugate is hydrolyzed by gut enzymes such as predominant. Chloramphenicol glucuronide, for ex- depends on the rate of respiration and pulmonary blood ample, is secreted into the bile, where it is hydrolyzed by flow. Such a The degree of solubility of a gas in blood also will af- continuous recirculation may lead to the appearance of fect the rate of gas loss.

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Under these conditions the increased demand placed on the myocardium cannot be met by the diminished arterial supply erectile dysfunction treated by buy 30 gm himcolin visa. It is situated dilating (angioplasty) psychological erectile dysfunction wiki buy himcolin online now, or surgically bypassing (coronary artery bypass near the top of the crista terminalis erectile dysfunction cure video purchase himcolin australia, below the superior vena caval grafting) erectile dysfunction pump how do they work himcolin 30 gm purchase with mastercard, the arterial stenosis erectile dysfunction doctor michigan himcolin 30 gm order without a prescription. Ischaemic heart disease is the leading cause of death in the tion pathway can lead to dangerous interruption of heart rhythm. The bundle of His divides into right and left branches which send There is considerable variation in size and distribution zones of the Purkinje fibres to lie within the subendocardium of the ventricles. For example, in some people the posterior interven- position of the Purkinje fibres accounts for the almost synchronous tricular branch of the right coronary artery is large and supplies a large contraction of the ventricles. The nerve supply of the heart Similarly, the sinu-atrial node is usually supplied by a nodal branch The heart receives both a sympathetic and a parasympathetic nerve of the right coronary artery but in 30–40% of the population it receives supply so that heart rate can be controlled to demand. Pulmonary trunk They are all covered with Left auricle Posterior pulmonary plexus the mediastinal pleura Sympathetic trunk Phrenic nerve Descending aorta Left ventricle Greater splanchnic nerve Oesophageal plexus on oesophagus Subclavian artery Oesophagus Subclavian vein Trachea Left brachiocephalic Vagus nerve vein Superior vena cava Pulmonary artery Acending aorta Fig. Here the right phrenic enters the caval opening and immediately penetrates the The thoracic sympathetic trunk (Figs 9. It descends in the thorax behind the pleura immediately lateral to costal vein to descend in front of the left lung root onto the pericardium the vertebral bodies and passes under the medial arcuate ligament of the overlying the left ventricle. Note: the phrenic nerves do not pass The thoracic chain bears a ganglion for each spinal nerve; the first beyond the undersurface of the diaphragm. However, they also transmit fibres which are sensory preganglionic fibres from its corresponding spinal nerve and sends to the fibrous pericardium, mediastinal pleura and peritoneum as well back a grey ramus, bearing postganglionic fibres. Upper limb sympathectomy is used for the treatment of hyperhidro- Irritation of the diaphragmatic peritoneum is usually referred to the sis and Raynaud syndrome. Hence, upper abdominal pathology such as a perfor- of part of the thoracic sympathetic chain (usually for two interspaces) ated duodenal ulcer often results in pain felt at the shoulder tip. It finally reaches the lower oesophagus where it visceraathe heart and great vessels, the lungs and the oesophagus. From this plexus, Mainly preganglionic fibres from T5–12 form the splanchnic nerves, anterior and posterior vagal trunks descend (carrying fibres from both which pierce the crura of the diaphragm and pass to the coeliac and left and right vagi) on the oesophagus to pass into the abdomen through renal ganglia from which they are relayed as postganglionic fibres to the oesophageal opening in the diaphragm at the level of T10. It is itself crossed here by the left superior intercostal (T5–10), lesser splanchnic (T10–11) and lowest splanchnic (T12). Below, it descends behind the lung root to reach the oesophagus They lie medial to the sympathetic trunk on the bodies of the thoracic where it contributes to the oesophageal plexus mentioned above (see vertebrae and are quite easily visible through the parietal pleura. The cardiac plexus Vagal branches This plexus is for descriptive purposes divided into superficial and deep The left recurrent laryngeal nerve arises from the left vagus below parts. The nerves of the thorax 25 10 Surface anatomy of the thorax Cervical plexus 2 2 4 4 Cardiac notch of lung Transverse fissure 6 6 Oblique fissure Costodiaphragmatic recess 8 8 10 10 Apex of lower lung Oblique fissure 6 Beginning of transverse fissure 8 Costodiaphragmatic recess Fig. The areas of auscultation for the aortic, pulmonary, mitral and tricuspid valves are indicated by letters 26 Thorax The anterior thorax pleura passes laterally for a small distance at the 4th costal cartilage and Landmarks of the anterior thorax include: descends vertically lateral to the sternal border to the 6th costal cartil- The angle of Louis (sternal angle): formed by the joint between the age. It is an important landmark as the cross the 8th rib in the mid-clavicular line, the 10th rib in the mid- 2nd costal cartilages articulate on either side and by following this line axillary line and finally reach the level of the 12th rib posteriorly. The apex and mediastinal border of the right lung follow the pleural The suprasternal notch: situated in the midline between the medial outline. In mid-inspiration the right lung lower border crosses the 6th ends of the clavicles and above the upper edge of the manubrium. The oblique fissures separate the lungs into upper The first palpable spinous process is that of C7 (vertebra prominens). The The transverse fissure: is represented by a line drawn horizontally spinous processes of the thoracic vertebrae can be palpated and counted from the 4th costal cartilage to a point where it intersects the oblique in the midline posteriorly. The fissure separates the upper and middle lobes of the right The scapula is located on the upper posterior chest wall. The heart The borders of the heart are illustrated by joining the four points Lines of orientation shown (Fig. These are imaginary vertical lines used to describe locations on the The apex of the left ventricle corresponds to where the apex beat is chest wall. The surface marking for the apex beat is in the 5th intercostal The mid-clavicular line: a vertical line from the midpoint of the clav- space in the mid-clavicular line. The anterior and posterior axillary lines: from the anterior and poster- ior axillary folds, respectively, vertically downwards. The great vessels Themid-axillary line: from the midpoint between anterior and poster- The aortic arch: arches antero-posteriorly behind the manubrium. The brachiocephalic artery and left common carotid artery: ascend Vertebral levels posterior to the manubrium. Palpable bony prominences can be used to identify the location of The brachiocephalic veins: are formed by the confluence of the inter- important underlying structures. This occurs posterior to the sterno- their corresponding vertebral levels are given: clavicular joints. The superior vena cava: is formed by the confluence of the left and Sternal angle (angle of Louis): T4/5. The position of the nipple is variable The trachea in the female but in the man it is usually in the 4th intercostal space in The trachea commences at the lower border of the cricoid cartilage (C6 the mid-clavicular line. It runs downwards in the midline and ends slightly to the right by bifurcating into the left and right main bronchi. The lines of pleural reflection pass behind the sternoclavicu- In mid-inspiration the highest part of the right dome reaches as far as lar joints to meet in the midline at the level of the sternal angle. Surface anatomy of the thorax 27 11 The abdominal wall Serratus anterior Cut edge of external oblique Linea alba Linea semilunaris Cut edge of external oblique Internal oblique Fig. Internal oblique A: above the costal margin Inferior B: above the umbilicus epigastric Transversus abdominis C: above the pubic symphysis artery Peritoneum 28 Abdomen and pelvis (a) External oblique aponeurosis Superficial ring Ilioinguinal nerve Femoral artery and vein in Spermatic cord femoral sheath Femoral canal (b) Testicular artery and Transversus pampiniform plexus of veins Position of deep ring Vas deferens Lymphatics Internal oblique Transversalis fascia Internal spermatic Position of fascia superficial ring Cremasteric fascia and Femoral artery and vein in muscle (striated) femoral sheath Femoral canal External spermatic fascia Fig. The external spermatic fascia has been removed (b) After removal of the external oblique Internal thoracic Anterior cutaneous branches of Musculophrenic intercostal nerves T7 Superior epigastric T10 T12 Lumbar Iliohypogastric (lateral branch) Para-umbilical veins Iliohypogastric anastomose with (anterior cutaneous) epigastric veins Ilioinguinal Fig. The two lower intercostal and four lumbar arteries supply the extraperitoneal fat, and parietal peritoneum. A deep fibrous (membranous) layeraScarpa’s fasciaawhich fades above and laterally but below blends with the fascia lata of the thigh The inguinal canal (Fig. These comprise: external oblique, internal oblique, transversus abdo- The superficial ring: is not a ring but a triangular-shaped defect in minis, rectus abdominis and pyramidalis (see Muscle index, p. It contains also the super- Superior: internal oblique arches posteriorly to form the roof of the ior and inferior epigastric vessels and anterior rami of the lower six canal. Posterior: transversalis fascia forms the lateral part of the posterior The sheath is made up from the aponeuroses of the muscles of the wall. The linea alba represents the fusion of the nal oblique and transversus into the pectineal line) forms the medial aponeuroses in the midline. The composition of the sheath Contents of the inguinal canal is, however, different above the costal margin and above the pubic The spermatic cord (or round ligament in the female). Above the costal margin: only the external oblique aponeurosis is present and forms the anterior sheath. The lateral border of the rectusathe linea semilunarisacan usually Cremasteric fascia and muscle: from the internal oblique be identified in thin subjects. Three tendinous intersections firmly attach the anterior sheath wall The contents of the spermatic cord include the: to the muscle itself. Pampiniform plexus of veins: these coalesce to form the testicular vein in the region of the deep ring. Short gastric Red labels: ventral branches Spleen Blue labels: lateral branches Green labels: branches to body wall Gastroduodenal Superior Pancreatic pancreatico- branches duodenal Left Right gastroepiploic gastro- epiploic Omental branch Inferior pancreatico- duodenal Jejunal and Superior ileal branches Superior mesenteric pancreaticoduodenal artery Inferior Fig. Superior The three primary branches are labelled in red mesenteric Middle colic Jejunal and ileal branches Right colic Ileocolic Anterior and posterior caecal branches Fig. Note the anastomosis with the inferior rectal artery (green) halfway down the anal canal The abdominal aorta (Fig. These include the: Ileocolic artery: passes in the root of the mesentery over the right Left gastric artery: passes upwards to supply the lower oesophagus ureter and gonadal vessels to reach the caecum where it divides into ter- by branches which ascend through the oesophageal hiatus in the minal caecal and appendicular branches (Fig. The left gastric then descends in the lesser omentum along Jejunal and ileal branches: a total of 12–15 branches arise from the the lesser curve of the stomach which it supplies. These branches divide and reunite within the Splenic artery: passes along the superior border of the pancreas small bowel mesentery to form a series of arcades which then give rise in the posterior wall of the lesser sac to reach the upper pole of the left to small straight terminal branches which supply the gut wall. From here it passes to the hilum of the spleen in the lienorenal Right colic artery: passes horizontally in the posterior abdominal ligament. Hepatic artery: descends to the right towards the first part of the The renal arteries duodenum in the posterior wall of the lesser sac. Before reaching the porta hepatis it divides into right and left on the posterior abdominal wall to reach the ovary in the female, or pass hepatic arteries and from the right branch the cystic artery is usually through the inguinal canal in the male to reach the testis. Prior to its ascent towards the porta hepatis the hepatic artery gives rise to gastroduodenal and right gastric branches. The former The inferior mesenteric artery arises from the abdominal aorta at the passes behind the first part of the duodenum and then branches further level of L3. It passes downwards and to the left and crosses the left into superior pancreaticoduodenal and right gastroepiploic branches. The left colic artery: supplies the distal transverse colon, the splenic flexure and upper descending colon. From above downwards, it passes over the left renal vein The superior rectal artery: passes into the pelvis behind the rectum behind the neck of the pancreas, over the uncinate process and anterior to form an anastomosis with the middle and inferior rectal arteries. This establishes a strong branches of the superior mesenteric artery include the: collateral circulation throughout the colon. The arteries of the abdomen 33 13 The veins and lymphatics of the abdomen Inferior phrenic Suprarenal Ureteric branch Renal Lumbar Gonadal Common iliac Median sacral Fig. Note the anastomoses with the systemic system (orange) in the oesophagus and the anal canal 34 Abdomen and pelvis The portal vein (Fig. Effer- to the liver where the products of digestion can be metabolized and ent lymph from the skin below the umbilicus drains to the superficial stored. The portal vein is formed behind the neck of the pancreas by the union of the superior mesenteric and splenic The lymph nodes and trunks veins. It passes behind the first part of the duodenum in front of the in- The two main lymph node groups of the abdomen are closely related to ferior vena cava and enters the free border of the lesser omentum. At the porta hep- of the aorta and consequently receive lymph from the territories that are atis it divides into right and left branches. This includes most of the gastrointestinal the branches of the coeliac and superior mesenteric arteries drain into tract, liver, gall-bladder, spleen and pancreas. The inferior mesenteric vein the pre-aortic nodes coalesce to form a variable number of intestinal drains into the splenic vein adjacent to the fourth part of the duodenum. The para-aortic nodes are arranged around the lateral branches of the Porto-systemic anastomoses aorta and drain lymph from their corresponding territories, i. The efferent vessels from the para-aortic nodes coalesce to form (such as in cirrhosis) the pressure within the portal vein rises and under a variable number of lumbar trunks which deliver the lymph to the cis- these circumstances the porto-systemic anastomoses form an alternat- terna chyli. The periumbilical region: formed by small paraumbilical veins The lymphatic drainage of the stomach which drain into the left portal vein and the superficial veins of the anter- Lymph from the stomach drains to the coeliac nodes. It ascends in the retroperitoneum on the right Lymph from the skin of the scrotum and the tunica albuginea drains to side of the abdominal aorta. Lymph from the testes, however, drains forms the posterior wall of the epiploic foramen of Winslow and is along the course of the testicular artery to the para-aortic group of embedded in the bare area of the liver in front of the right suprarenal nodes. The inferior vena cava passes through the caval opening in the enlargement of the superficial inguinal nodes whereas testicular diaphragm at the level of T8 and drains into the right atrium. The veins and lymphatics of the abdomen 35 14 The peritoneum Subphrenic space Diaphragm Epiploic foramen (of Winslow) Upper recess of omental bursa Portal vein Inferior vena cava Liver Aorta Lesser omentum Epiploic foramen Left kidney (in the distance) Splenic artery Omental bursa Pancreas Lienorenal ligament Stomach Spleen Transverse mesocolon Short gastric Duodenum (third part) vessels Transverse colon Gastrosplenic Small intestine ligament Stomach Mesentery Lesser omentum Greater omentum Hepatic artery Fusion between layers Common bile duct of greater omentum Liver Fig. Note how the epiploic foramen lies between two major veins Lesser sac Greater sac Upper layer of Upper layer of Left triangular coronary ligament coronary ligament Bare area ligament Lower layer of coronary ligament Gall bladder B Ligamentum teres A Portal vein, hepatic Falciform ligament artery and bile duct in free edge of lesser Ligamentum teres omentum leading to porta hepatis Position of umbilicus Cut edge of lesser Fundus of (b) omentum (a) gall bladder Left triangular Right Peritoneum ligament triangular covering Fissure for ligament caudate lobe ligamentum venosum Fig. The narrow spaces between the liver and the diaphragm labelled A and B are the right and left subphrenic spaces 36 Abdomen and pelvis The mesenteries and layers of the peritoneum ment while the right layer turns back on itself to form the upper and The transverse colon, stomach, spleen and liver each have attached to lower layers of the coronary ligament with its sharp-edged right tri- them two ‘mesenteries’adouble layers of peritoneum containing arteries angular ligament. The layers of the coronary ligament are widely and their accompanying veins, nerves and lymphaticsawhile the small separated so that a large area of liver between themathe bare areaa intestine and sigmoid colon have only one. This mesentery is exceptional in that the layers of the which passes from the hilum of the spleen to the greater curvature of the coronary ligament are widely separated so that the liver has a bare area stomach (Fig. The general peritoneal cavity comprises the main cavityathe greater The sigmoid colon: (1) The sigmoid mesocolon (the sigmoid arteries sacaand a diverticulum from itathe omental bursa (lesser sac). It lies behind the free border of tinue downwards to form the posterior two layers of the greater omen- the lesser omentum and its contained structures, below the caudate pro- tum, which hangs down over the coils of the small intestine. They then cess of the liver, in front of the inferior vena cava and above the first turn back on themselves to form the anterior two layers of the omentum part of the duodenum. The four layers of The subphrenic spaces are part of the greater sac that lies between the the omentum are fused and impregnated with fat. There are right and left plays an important role in limiting the spread of infection in the peri- spaces, separated by the falciform ligament. In the pelvis the parietal peritoneum covers the upper two-thirds of From its attachment to the pancreas, the lower layer of the transverse the rectum whence it is reflected, in the female, onto the posterior mesocolon turns downwards to become the parietal peritoneum of the fornix of the vagina and the back of the uterus to form the recto-uterine posterior abdominal wall from which it is reflected to form the mesen- pouch (pouch of Douglas). The upper layer of the transverse mesocolon passes upwards to form the parietal peritoneum of the posterior abdominal wall, covering the The anterior abdominal wall upper part of the pancreas, the left kidney and its suprarenal, the aorta The peritoneum of the deep surface of the anterior abdominal wall and the origin of the coeliac artery (the ‘stomach bed’). It thus forms the shows a central ridge from the apex of the bladder to the umbilicus pro- posterior wall of the omental bursa. Two medial umbilical ligaments converge to the From the diaphragm and anterior abdominal wall it is reflected onto umbilicus from the pelvis. They represent the obliterated umbilical the liver to form its ‘mesentery’ in the form of the two layers of the fal- arteries of the fetus. It represents the obliterated left folds back on itself to form the sharp edge of the left triangular liga- umbilical vein. The peritoneum 37 15 The upper gastrointestinal tract I Cardiac notch Lesser curvature Fundus Angular incisure Pyloric sphincter Body Duodenum Greater curvature Pyloric antrum Fig. The stomach is outlined but the shape is by no means constant 38 Abdomen and pelvis The embryonic gut is divided into foregut, midgut and hindgut, sup- verse colon. The anterior and posterior vagal trunks descend along the plied, respectively, by the coeliac, superior mesenteric and inferior lesser curve as the anterior and posterior nerves of Latarjet from which mesenteric arteries. The latter includes a supply The midgut extends down to two-thirds of the way along the transverse to the acid-secreting partathe body.

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It is highly corrosive and peripheral neuropathy erectile dysfunction doctors in alexandria va order discount himcolin on line, cerebellar disease and dementia; can be absorbed through the skin erectile dysfunction caused by ssri buy 30 gm himcolin fast delivery. A common sequence is: damage to the kidney erectile dysfunction devices buy himcolin 30 gm free shipping, liver yohimbine treatment erectile dysfunction cheap himcolin line, heart and lungs also occurs 8 ulceration and sloughing of the oral and oesophageal mu- with solvents erectile dysfunction treatment bodybuilding buy discount himcolin. Whether the patient lives of these cases there was no previous history of abuse, sug- gesting that death commonly occurs on the first use. Over 50% of deaths from the practice follow cardiac arrhythmia, 8A19-year-oldmalewasadmittedtohospitalinSriLanka,havingingested probably caused by sensitisation of the myocardium to cat- 250 mL of paraquat in an episode of deliberate self-harm. He was echolamines and by vagal inhibition from laryngeal stim- accompanied by his brother and friend. The unfortunate young man ulation due to aerosol propellants sprayed into the died within 8 h of admission. His brother and friend presented to the same hospital 2 days later with severe swelling and burns to the scrotal throat. They had originally brought the patient to hospital in a three- inhalation due to its particular tendency to induce cardiac wheeled taxi with the patient lying across their laps. They had been wearing sarongs which they had been unable to change out of during their 8-hour vigil before he died. The brother went on to develop evidence of mild systemic toxicity with Acute solvent poisoning requires immediate cardiorespi- abnormalities of renal and hepatic function. It is pos- may resemble one another closely and some are greatly sible that a physician will be called upon to treat individuals prized by epicures. Deaths from plant poisoning are thus disseminated as an aerosol (particles of 1 micron in diame- very rare in industrialised societies. Plant poisoning is, ground in minutes, so that the risk of prolonged exposure however, a significant problem in the developing world. In‘deathcap’(Amanita phalloides) solid aerosol or smoke; solutions (Mace) are used at close mushroom poisoning, high dose penicillin or silibi- quarters. Inadditiontotheusualprop- poisoning with plants that produce toxic cardiac erties(above)itmayinduceatransientriseinintraocularpres- glycosides. Emergency management of tricyclic department visits for acetaminophen- 134 Poisoning, overdose, antidotes Chapter | 10 | Evison, D. Non-opioid collide – why physicians participate in Pitfalls in the management of the analgesic poisoning. It Substance dependence is defined as: also results from metabolic changes (enzyme induction) and physiological or behavioural adaptation to drug ef- when an individual persists in use of alcohol or other fects, e. Physiological adaptation develops to a drugs despite problems related to use of the substance, substantial degree with cerebral depressants, but is minor substance dependence may be diagnosed. There is commonly cross- and repetitive use may result in tolerance to the effect tolerance between drugs of similar, and sometimes even of the drug and withdrawal symptoms when use is of dissimilar, chemical groups, e. A discontinuation (withdrawal) syndrome occurs, for Substance abuse is a term that is less clearly defined and example, when administration of an opioid is suddenly becoming less used, in favour of the term substance depen- stopped. Abrupt discontinuation results tion Producing Drugs 1957 defined substance abuse in the in an immediate deficiency of endogenous opioid, which context of two components: thus causes the withdrawal syndrome. There are again no absolute definitions of is a state of periodic or chronic intoxication produced these categories. Its characteristics include: (i) an individualasafunctioningmemberofsocietybyinducingse- overpowering desire or need (compulsion) to continue vere psychological and, in the case of cerebral depressants, taking the drug and to obtain it by any means; physicaldependence. Theremaybepsy- on the effects of the drug; and (iv) detrimental effects chological dependence, but there is little or no physical de- on the individual and on society. Thegroupincludessedativesandtranquillisers,amfetamines, cannabis, hallucinogens, alcohol, tobacco and caffeine. Substance habituation is a condition resulting from the This classification fails to recognise individual variation repeated consumption of a drug. Alcohol can be used in heavy doses that are (i) a desire (but not a compulsion) to continue taking the gravely disabling and induce severe physical dependence drug for the sense of improved well-being which it engen- with convulsions on sudden withdrawal; i. But there are many people mildly some degree of psychic dependence on the effect of the psychologically dependent on it who retain their position drug, but absence of physical dependence and hence of in the home and society. The subject not the drug but the effect it has on, or the way it is used may develop craving for the drug with anxiety, insomnia by, the individual. Those drugs 2Diagnostic and Statistical Manual of Mental Disorders, American with high dependence/abuse liability are subject to regula- Psychiatric Association 2007. Possession of these substances is not illegal; however, it is an offence to supply such a substance if it likely to be abused. Readers will be aware that the list is subject to change according to social factors and political expediency. Relief of anxiety, tension and depression; escape from relinquish heavy use as they enter personal psychological problems; detachment from middle age Also cannabis, magic mushrooms harsh reality; ease of social intercourse. Rebellion against or despair about orthodox social Any age Alcohol, tobacco, mild dependence on values and the environment. Improvement of performance in competitive sport while 1 in 10 had used an illicit substance in the previous (a distinct motivation, see below). The survey also allows observations on the trends in illicit drug use over time, as shown in Table 11. Patterns change as drugs Drugs of abuse are extremely diverse in their chemical struc- come in and out of vogue. Nevertheless, there is an emerging consensus that provided from a number of sources but up-to-date infor- addictive drugs possess a parallel ability to modulate the mation on prevalence and patterns of usage can be brain reward system that is key to activities that are vital for obtained from the annual British Crime Survey. It seems that drugs of abuse can converge on com- mon neural mechanisms in these areas to produce acute re- ward and chronic alterations in reward systems that lead to About £1. These are managed by either absti- nence or, more commonly, maintenance on prescribed al- Increasing evidence suggests that drugs of addiction all ternatives such as methadone. While obviously important, this is only a step on what can be a long and often disappoint- ing journey to psychological and social rehabilitation, e. With the intravenous route or inhalation, much higher 4 See Department of Health 1999 Drug Misuse and Dependence – peak plasma concentrations can be reached than with oral Guidelines on Clinical Management. More acutely, the physical features associated with discontinuing high alcohol use may be al- Young illicit users by intravenous injection (heroin, benzo- leviated by chlordiazepoxide given in decreasing doses for diazepines, amfetamine) have a high mortality rate. Sympathetic autonomic overactivity can be follows either overdose or the occurrence of septicaemia, treated with a b-adrenoceptor blocker. A less harmful drug by a less harm- heroin sometimes carry the drug in plastic bags concealed ful route may be substituted, e. Addicts are often particularly reluctant to abandon the intravenous route, which provides the ‘immediate high’ that they find, or originally found, so desirable. An abdominal radiograph showed a large number of spherical packages in his Severe pain in an opioid addict presents a special pro- gastrointestinal tract, and body-packing was suspected. He developed ventricular or overdose may result; low-efficacy opioids will not only fibrillation and died. Post-mortem examination showed that he had ingested more than 150 latex packets, each containing 5 g cocaine, be ineffective but may induce withdrawal symptoms, making a total of almost 1 kg (lethal oral dose 1–3 g). Sorbitol or lactulose with activated charcoal should be used to remove ingested packages, or surgery if there are signs of intoxication. Testosterone and its related compound, epitestosterone, are A variable proportion of subjects who start with cannabis both eliminated in urine. This disposition to progress from tosterone increases with use of anabolic steroids and can be occasional to frequent soft use of drugs through to hard used to detect anabolic steroid use. De-escalation also occurs as users become disillusioned Performance enhancement with drugs over about 10 years. This unhappily chosen term has been generally taken to re- In addition, owing to the recognition of natural biolog- fer to molecular modifications produced in secret for profit ical differences, most competitive events are sex segregated. The World Wide It seems safe to assume that anything that can be thought Web enables customers to order such ‘research chemicals’ up to gain advantage will be tried by competitors eager online from large laboratories based in countries where for immediate fame. No doubt placebo effects are important, It is then hard to detect such compounds entering the coun- i. Doctors should remem- ber that they may get their athlete patients into trouble with Globalisation and the use of the internet have spawned sports authorities by inadvertent prescribing of banned a large market for the development and sale of new substances. Detection can be difficult when thedrugs ormetabolites are closely related The World Health Organization recommends that drug to or identical with endogenous substances, and when the dependence be specified by type for purposes of detailed drug can be stopped well before the event without apparent loss of efficacy. Detection of levels of the nat- urally occurring compound above this level indicates 6A highly sensitive technique that can identify minor differences between potential doping. It is based on the principle that ions passing at high velocity through an electrical field at right angles to their motion will deviate exactly these benchmarks should be set. Research continues from a straight line according to their mass and charge; the heaviest for improved methods of detecting drugs used in sport. The gastrointestinal absorption of alcohol • phencyclidine, cannabis); taken orally is rapid as it is highly lipid soluble and diffus- psychostimulants (cocaine, amfetamines, ible. The major site of absorption is the small intestine; so- • methylxanthines, khat); lutions above 20% are absorbed more slowly because high volatile substances. Absorption is delayed by food, especially milk, the effect Ethyl alcohol (ethanol) of which is probably due to the fat it contains. Maximum blood concentrations 142 Drug dependence Chapter | 11 | after oral alcohol therefore depend on numerous factors in- Induction of hepatic drug-metabolising enzymes occurs with cluding: the total dose; sex; the strength of the solution; repeated exposure to alcohol. This contributes to tolerance the time over which it is taken; the presence or absence in habitual users, and to toxicity. Increased formation of of food in the stomach; the time relations of taking food metabolites causes organ damage in chronic over- and alcohol, and the kind of food eaten; the speed of me- consumption (acetaldehyde in the liver and probably fatty tabolism and excretion. Once the blood alysers) are used by police at the roadside on both drivers concentration exceeds about 10 mg/100 mL the enzymatic 7 and pedestrians. It seems likely that acetaldehyde * Cytochrome P450 acts synergistically with alcohol to determine the range of Catalase oxidase system neurochemical and behavioural effects of alcohol consump- Ethanol tion. Psychic effects are Ethanoate (acetate) the most important socially, and it is to obtain these that the drug is habitually used in so many societies, to make social intercourse not merely easy but even pleasant. AcetylCoA sythetase Environment, personality, mood and dose of alcohol are all relevant to the final effect on the individual. Alcohol in ordinary doses may act chiefly on the arousal mechanisms of the brainstem reticular formation, inhibit- Acetyl CoA ing polysynaptic function and enhancing presynaptic inhi- bition. Direct cortical depression probably occurs only with 7An arrested man was told, in a police station by a doctor, that he was Tricarboxylic acid cycle Protein and fat biosynthesis drunk. The man asked, ‘Doctor, could a drunk man stand up in the middle of this room, jump into the air, turn a complete somersault, and land down on his feet? The introduction of the breathalyser, which has a statutory role only in road traffic situations, Fig. There is a decline through all the stages of general anaesthesia and may die in attentiveness and ability to assimilate, sort and take from respiratory depression. Loss of consciousness occurs quick decisions on continuously changing information at blood concentrations around 300 mg/100 mL, death at input; an example is inattentiveness to the periphery of about 400 mg/100 mL. All of these are clearly highly undesirable effects when a Innumerable tests of physical and mental performance person is in a position where failure to perform well may be have been used to demonstrate the effects of alcohol. Some other important physiological and meta- Results show that alcohol reduces visual acuity and delays bolic effects of acute alcohol ingestion are described in recovery from visual dazzle, impairs taste, smell and hear- Table 11. It com- changes, excitement, mental confusion (including ‘black- monly increases subjects’ confidence in their ability to outs’), incoordination and even coma. Numerous other perform well when tested and tendency to underestimate conditions can mimic this presentation and diagnosis Table 11. Alcohol can cause severe hypoglycae- For this reason, the compulsory use of a roadside breath mia; measurement of blood alcohol may clarify the situa- test is acknowledged to be in the public interest. Chronic consumption Where blood or breath analysis is not immediately avail- able after an accident, it may be measured hours later and Tolerance to alcohol can be acquired and the point has ‘back calculated’ to what it would have been at the time of been made that it costs the regular heavy drinker 2. It is usual to assume that the blood concentra- as much to get visibly drunk as it would cost the average tion falls at about 15 mg/100 mL/h. When wine rationing was introduced in Paris during the Second World Alcohol dependence is a complex disorder with environ- War, deaths from hepatic cirrhosis dropped to about one- mental, drug-induced and genetic components with sixth of the previous level; 5 years after the war they had multiple genes probably contributing to vulnerability to regained their former level. In practice, prosecutions are undertaken only when the concentration is significantly higher to avoid arguments about biological variability and instrumental error. Urine The effects of alcohol and psychotropic drugs on motor car concentrations are little used as the urine is accumulated over time and does not provide the immediacy of blood and breath. Due to 146 Drug dependence Chapter | 11 | the risk of over- or under-prescribing, increasingly symp- a test dose of alcohol under supervision (after the 5th day tom-triggered prescribing is used to facilitate the inpatient of taking), so that patients can be taught what to expect, detoxification. This remains an extremely active area of It is usual to administer vitamins, especially thiamine, in research. But both patients use, but it carries significant risk of dependence and should and non-patients justifiably expect some guidance, and not be given if the patient is likely to persist in drinking doctors and government departments will wish to be alcohol. In other societies recom- needs to be recognised early due to very high mortality mended maxima are higher or lower. The type of drink (beer, wine, spirits) is not particularly Treatment of alcohol dependence relevant to the adverse health consequences; a standard Psychosocial support is more important than drugs, which bottle of spirits (750 mL) contains 300 mL (240 g) of al- nevertheless may help. Iftakenfor1 year(accompanied of cognitive decline,11and light-to-moderate alcohol con- by counselling and psychosocial support), acamprosate in- sumption may reduce risk of dementia in people aged creases the number of alcohol-free days and also the chance 55 years or more. The benefit may last for The curve that relates mortality (vertical axis) to alcoholic 1 year after stopping treatment. As con- Acamprosate may cause diarrhoea, and cutaneous sumption rises above zero the all-cause mortality declines, eruptions. The benefit is largely a reduction of deaths due to cardiovascular and Disulfiram (Antabuse) discourages drinking by inducing cerebrovascular disease for regular drinkers of 1–2 units immediate unpleasantness. It is an aldehyde dehydroge- per day for men aged over 40 years and postmenopausal nase inhibitor, so that acetaldehyde (a toxic metabolite women.

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Mufassa, 26 years: Expression of virus-induced neoplasia may also depend on additional host and environmental factors that modulate the transformation process. Rounding this dose to an amount available as an oral dosage form, 1200 mg of lithium carbonate would be given every 12 hours.

Arakos, 50 years: These cellular alterations result from endocytosis of modified lipoproteins via at least four species of scavenger receptors. Oral opioid therapy for reports experiencing severe migraine attacks that cause her to miss chronic peripheral and central neuropathic pain.

Pranck, 58 years: Use of diuretics such as thiazides or loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism. The basal ganglia: axial anatomic cut through the bodies of the lateral ventricles, displaying the rostrocaudal extent of the caudate nuclei, superior to the level of lenticular nuclei.

Oelk, 54 years: Compounds in this category of drug interactions include aminoglycoside antibi- otics, vancomycin, cotrimoxazole (trimethoprim-sulfamethoxazole), amphotericin B, cis- platin, and nonsteroidal antiinflammatory drugs. Tinctures, lotions, gels, foams, and aerosols are convenient for application to the scalp and hairy areas.

Barrack, 59 years: The naturally occurring estrogens and progestins The ovary is the major site of estrogen and progestin are not orally active because they are rapidly metaboli- biosynthesis in nonpregnant premenopausal women. However, this can be greatly modified by the use of other sedatives as well as by associated factors (eg, diabetes, injury).

Kapotth, 42 years: Free movement of the tendons in the channels is Tarsal tunnel, retinacula, and arrangement facilitated by synovial sheaths, which surround the of major structures at the ankle tendons. The major toxicity of thiazide diuretics, besides hypokalemia, hypomagnesemia, and hyperglycemia, is hypercalcemia.

Ramirez, 38 years: Drugs such as acetaminophen cause necrosis in the centrilobular portion of the liver at a site Pulmonary Toxicity of the monooxygenase enzymes that bioactivate the analgesic. Clinicians should always con- sult the patient’s chart to confirm that current antiarrhythmic and other drug therapy is appropriate.

Thorus, 32 years: In addition, the nerve of the pterygoid canal enters • The foramen rotundum and pterygoid canal communi­ the fossa carrying: cate with the middle cranial fossa and open onto the posterior wall. The fluid may be removed by a needle tap or thoracocentesis, and, in some cases, it may be necessary to ligate the duct.

Rune, 52 years: Superior to the umbo in an anterior direction is the Exteral ear attachment of the rest of the handle of the malleus (Fig. Systemically ad- impulses passing down the postganglionic sympathetic ministered -methyldopa rapidly enters the brain, (and parasympathetic) nerves, decreases vascular tone, where it accumulates in noradrenergic nerves, is con- cardiac output, and blood pressure.

Abbas, 33 years: There is, however, no evidence that this has actually translated into increased incidence of arrhythmias. Methoxy polyethylene glycol-epoetin beta should not be used for treatment of anemia caused by cancer chemotherapy because a clinical trial found significantly more deaths among patients receiving this form of erythropoietin.

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