Pradeep Chopra, MD

• Assistant Professor (Clinical)
• Department of Medicine
• Boston University School of Medicine
• The Warren Alpert Medical School
• Providence, Rhode Island

Transection of the left gastric artery at its origin during gastrectomy may cause ischaemic necrosis of the left hemiliver if a replaced left artery is present depression definition webmd purchase 10mg anafranil. The same may occur on the right side as a result of injury to a replaced right artery depression definition causes buy anafranil no prescription. This anomaly may be suspected when depression test com cheap anafranil 75 mg with visa, on opening the peritoneum at the base of the right side of the hepatoduodenal ligament mood disorder marriage order anafranil in india, the portal vein is immediately apparent instead of the hepatic artery depression mood definition generic 50 mg anafranil otc. For instance anxiety untreated order 10mg anafranil fast delivery, when a replaced left artery supplies the left lateral section it is possible to resect the entire proper hepatic artery when performing a right trisectionectomy for hilar cholangicarcinoma. The replaced right artery is sometimes invaded by pancreatic head tumours and is in danger of injury during pancreato-duodenectomy. There are many variations of replaced arteries, especially on the right, depending on the relationships of the artery to the pancreatic head and neck, the bile duct and the portal vein. One important anatomical point is that an artery located to the right side of the bile duct always supplies the right side of the liver, but arteries found on the left side of the bile duct may supply either side of the liver. Therefore, when using the individual vessel ligation method it is important to be aware of the position of the common hepatic duct. A trial occlusion of an artery with an atraumatic clamp should always be performed in order to be sure that there is a good pulse to the side of the liver to be retained. The sectional ducts unite to form the right hepatic duct, which unites with the left hepatic duct at the confluence to form the common hepatic duct. A right sectional bile duct inserting into the left hepatic duct is in danger of injury during left hepatectomy if the left duct is divided at its termination. Therefore, when performing left hepatectomy, the left hepatic duct should be divided close to the umbilical fissure to avoid injury to a right sectional duct. The second important anomaly is insertion of a right bile duct into the biliary tree at a lower level than the prevailing site of confluence. Low union may affect the right hepatic duct, a sectional right duct (usually the anterior one), a segmental duct or a subsegmental duct. A right bile duct unites with the common hepatic duct below the prevailing site of confluence in about 2% of individuals. Sometimes the duct unites with the cystic duct and then with the common hepatic duct. The latter anomaly places the aberrant duct at great risk of injury during laparoscopic cholecystectomy. In the latter case a gallstone has effaced a cystic duct which united with the right hepatic duct, giving the appearance that it joins the gallbladder. In these cases the right and left hepatic duct Bile ducts and liver resections Prevailing pattern and important variations of bile ducts draining the right hemiliver Normally only a short portion of the right hepatic duct, about 1 cm, is in an extrahepatic position. In the prevailing pattern, the segmental ducts from Sg2 and Sg3 (B2, B3) unite to form the left lateral sectional bile duct. This duct passes behind the umbilical portion of the portal vein and unites with the duct from segment 4 (B4; also called the left medial sectional duct since section and segment are synonymous for this volume of liver). Note that it is in an extrahepatic position and that it has a much longer extrahepatic course than the right bile duct. In the latter instance, which according to Couinaud is present in 8% of individuals, there is no left hepatic duct. Instead there is a confluence of three ducts, the left lateral sectional duct, B4 and the right hepatic duct to form the common hepatic duct. These variations are important in split liver transplantation and in diagnosis and repair of biliary injuries. The bile duct to Sg3 has been used to perform biliary bypass and can be isolated by following the superior surface of the ligamentum teres down to isolate the portal pedicle to Sg3. The technique is less commonly used now that internal endoscopic bypass has been developed. Prevailing pattern of bile ducts draining the caudate lobe (Sg1) Normally, two to three caudate ducts enter the biliary tree. Their orifices are usually located posteriorly on the left duct, right duct or right posterior sectional duct. Portal veins and liver resections On the right side of the liver the portal vein divisions correspond to those of the hepatic artery and bile duct, and they supply the same hepatic volumes. It divides into two sectional and four segmental veins, as do the arteries and bile ducts. On the left side of the liver, however, the left portal vein is quite unusual because of the fact that its structure was adapted to function in utero as a conduit between the umbilical vein and the ductus venosus, whilst postnatally the direction of flow is reversed. Unlike the right portal vein, neither portion of the left portal vein actually enters the liver, but rather they lie directly on its surface. Often the umbilical portion is hidden by a bridge of tissue passing between left medial and lateral sections. Large branches from the portal vein to the left liver arise exclusively beyond the attachment of the ligamentum venosum, i. There is usually only one branch to Sg2 and Sg3, but often there is more than one branch to Sg4. The left portal vein terminates in the ligamentum teres at the free edge of the left liver. This is also the site of origin of the ligamentum venosum, where the transverse portion of the left portal vein becomes the umbilical portion of the vein, proving conclusively that the branch to Sg2 is not part of a terminal division of the transverse portion of the vein as might be concluded from case studies (also see Ref. The pattern is similar to an air-conditioning duct that sends branches at right angles from both of its sides to supply rooms (segments), tapering as it does so, finally to end blindly (in the ligamentum teres). Other vascular and biliary structures normally ramify by dividing into two other structures at their termination and not by sending out branches along their length. Although the divisions of the portal vein are unusual, for the embryonic reasons described above, it is uncommon to have variations from this pattern. In these cases the right posterior and right anterior sectional portal veins originate independently from the main portal vein. Under these circumstances the anterior sectional vein is usually quite high in the porta hepatis and may not be obvious. An unsuspecting surgeon may divide the posterior sectional vein thinking that it is the right portal vein and become confused when the anterior sectional vein is subsequently revealed during hepatic transection. The apparent right vein is really the main portal vein, a structure that enters the liver, gives off branches to the right liver and then loops back within the liver substance to supply the left side. The presence of the transverse portion of the left vein at the base of Sg4, which then enters the umbilical fissure, precludes the presence of this anomaly. The portal vein branches to Sg4 may be isolated in the umbilical fissure on the right side of the umbilical portion of the left portal vein. The veins here are associated with the bile ducts and the arteries passing to Sg4, i. Isolation in this location may provide extra margin when resecting a tumour in Sg4 that impinges upon the umbilical fissure. Normally the branches to Sg4 are isolated after dividing the parenchyma of the liver of Sg4 close to the umbilical fissure, an approach that is used to avoid injury to the umbilical portion of the left portal vein. Injury to this vein could, of course, deprive Sg2 and Sg3 of portal vein supply as well as Sg4. For instance, if this occurs when performing a right trisectionectomy, the only portion of the liver to be retained would be devascularised of portal vein flow. However, isolation of these structures within the umbilical fissure does provide an extra margin of clearance on tumours and can be done safely if care is taken to ascertain the position of the portal vein. Likewise, it is possible to isolate the portal vein branches going into Sg2 and Sg3 in the umbilical fissure and to extend a margin when resecting a tumour in the left lateral section. For the same reasons given above, caution must be taken when doing this in order not to injure the umbilical portion of the portal vein. In order to access the portal vein in this location it is usually necessary to divide the bridge of liver tissue, between the left medial and lateral sections. This is done by passing a blunt instrument behind the bridge before dividing it, usually with cautery. To facilitate passage of an instrument behind the bridge, the peritoneum at the base of the bridge may be opened in a preliminary step. These run in the midplane of the liver (middle hepatic vein), the right intersectional plane (right hepatic vein) and the left intersectional plane (left hepatic vein). The left hepatic vein actually begins in the plane between Sg2 and Sg3 and travels in that plane for most of its length. Note that this is the same plane in which the umbilical portion of the left portal vein lies. The latter is proof that the terminal portion of the left vein lies in the intersectional plane of the left liver. In the presence of this vein, resections of Sg7 and Sg8 may be performed, including resection of the right superior vein, without compromising the venous drainage of Sg5 and Sg6. When performing a classical right hepatectomy, caudate veins are divided in the preliminary stage of the dissection. This bridge of tissue usually consists of fibrous tissue, but occasionally is a bridge of liver parenchyma. Another approach to right hepatectomy is to leave division of the caudate and right hepatic veins until after the liver is transected. In this case a clamp may be passed up along the anterior surface of the vena from below to emerge between the right and middle hepatic veins. This exposes the entire anterior surface of the retrohepatic vena cava and leaves the liver attached to the vena cava only by the middle and left hepatic veins, which are then easily isolated. This is suitable when performing a right hepatectomy or extended right hepatectomy, especially when the caudate lobe is also to be resected. In performing a left hepatectomy the right hepatic vein is conserved and a different anatomical approach to isolation of the left and middle hepatic veins is required. They may be isolated from the left side by dividing the ligamentum venosum, where it attaches to the left hepatic vein, then dividing the peritoneum at the superior tip of the caudate lobe and gently passing an instrument on the anterior surface of the vena cava to emerge between the middle and right veins and/or between the left and middle veins. Again, care needs to be applied when performing this manoeuvre in order to avoid injury to the structures. Isolation of the vena cava above and below the hepatic veins is also a technique that should be in the armamentarium of every surgeon performing major hepatic resection. It is not usually necessary when performing standard liver resections but surgeons should be familiar with the anatomical technique of doing so. Isolation of the vena cava superior to the hepatic veins is done by dividing the left triangular ligament and the lesser omentum, being careful to first look for a replaced left hepatic artery. Next the peritoneum on the superior border of the caudate lobe is divided and a finger is passed behind the vena cava to come out just inferior to the crus of the diaphragm. This column passes across the right side of the vena cava and dissection of the space inferior to this column and behind the vena cava facilitates passage of the finger from the left side to the right side in the space behind the vena cava. Isolation of the vena cava below the liver is more straightforward but one should be aware of the position of the adrenal vein and in some cases it is necessary to isolate the adrenal vein if bleeding is persisting after occlusion of the vena cava above and below the liver. Finally, the surgeon should be aware that during transection of the liver large veins will be encountered in certain planes of transection. The venous drainage of the right side of the liver is highly variable and additional large veins, including one from Sg6, may also enter the middle hepatic vein. It is a mostly flat structure, which lies principally in the coronal plane, posterior to the main bilovascular structures in the porta hepatis. However, its upper border is curved, so that it has the shape of a toboggan when viewed in the sagittal plane. This upper curved edge lies superior to the right and left bile ducts, the most superior structures in the porta hepatis. The sheath of the right portal pedicle extends off the hilar plate like a sleeve into the liver surrounding Sheath the portal structures, i. As the right portal pedicle enters the liver it divides into a right anterior and right posterior portal pedicle supplying the respective sections, and then segmental pedicles supplying the four segments. There is no sheathed main portal pedicle because the main portal vein, proper hepatic artery and common hepatic duct are not close enough to the liver to be enclosed in a sheath. In its posterior extent the cystic plate narrows to become a stout cord that attaches to the anterior surface of the sheath of the right portal pedicle. The latter is a point of anatomical importance for the surgeon wishing to expose the anterior surface of the right portal pedicle, since this cord must be divided to do so, as we have described. The other sheaths carry segmental bilovascular pedicles of the left liver and caudate lobe. In performing a right hepatectomy there are two methods of managing the right-sided portal vessels and bile ducts. The first is to isolate the hepatic artery, portal vein and bile duct individually and either control them or ligate them extrahepatically, and the second is to isolate the entire portal pedicle and staple the pedicle. Isolation of the right portal pedicle can be performed by making hepatotomies above the right portal pedicle in Sg4 and in the gallbladder fossa after removing the gallbladder. The bare area stretches superiorly to include the termination of the three hepatic veins and ends in a point, which is also where the attachment of the falciform ligament ends. The limit of the bare area, where the peritoneum passes between the body wall and the liver, is called the coronary ligament. The other ligamentous structures of interest to surgeons are the ligamentum teres, falciform ligament and the ligamentum venosum. The umbilical tape in the upper right of the photograph is around the bridge of liver tissue over the umbilical fissure. Fissure and scissure or scissura are similarly confusing terms since they apply only to clefts in casts of the liver. The ligaments of the liver are of surgical importance and are described under capsule and attachments. Pathological conditions may distort or alter the position of normal hepatic structures.

Paralysis of soft palate due to diphtheria depression from work purchase anafranil overnight, bulbar palsy bipolar depression treatment resistant order anafranil master card, cerebrovascular accidents depression symptoms diarrhea buy anafranil. Ascertain anxiety 4 year old symptoms buy cheap anafranil line, if dysphagia is of: (a) Sudden onset: Foreign body or impaction of food on a preexisting stricture or malignancy depression symptoms acronym cheap anafranil 50 mg with visa, neurological disorders depression symptoms uk quality 25mg anafranil. Examination of the neck, chest and nervous system, including cranial nerves should also be undertaken. To exclude cervical osteophytes and any soft tissue lesions of postcricoid or retropharyngeal space. It is useful in the diagnosis of malignancy, cardiac achalasia, strictures, diverticula, hiatus hernia or oesophageal spasms. Combined with fluoroscopic control or cineradiography, it can help in the diagnosis of motility disorders of oesophageal wall or sphincters. A pressure transducer along with a pH electrode and an open-tipped catheter is introduced into the oesophagus to measure the pressures in the oesophagus and at its sphincters. It also measures the effectiveness of oesophagus to clear the acid load after acid solution is put in the oesophagus. These studies help in motility disorders, gastro-oesophageal reflux and to find whether oesophageal spasms are spontaneous or acid induced. Bronchoscopy (for bronchial carcinoma), cardiac catheterization (for vascular anomalies), thyroid scan (for malignant thyroid) may be required, depending on the case. It can be removed as an office procedure by asking the patient to hold his own tongue while examiner holds a large laryngeal mirror or an endoscope in one hand and a curved forceps in the other. Sometimes a sharp needle in the base of tongue may get totally embedded into its substance due to repeated attempts to feel. Once in muscular layers, it has a chance to migrate and an early removal is indicated. Most of them can be seen with oropharyngeal examination under good illumination and removed with a forceps. Fish bone, chicken or a mutton bone, needle or a denture may lodge in the pyriform fossa. Small foreign bodies can be removed under local anaesthetic with a curved forceps as described above. Large impacted foreign bodies or those in children should be removed by endoscopy under general anaesthesia. Usual foreign bodies that get lodged in the oesophagus are a coin, piece of meat, chicken bone, denture, safety pin or a marble. Sometimes other object like nails, screws, plastic objects or pieces of glass may also be seen. Disc batteries are also becoming common these days due to their wide spread usage. Most of oesophageal foreign bodies lodge just below the cricopharyngeal sphincter. If they lodge lower down, an underlying condition such as congenital or acquired stricture or a malignancy (in adults) should be suspected and/or a follow-up barium swallow should be done when oedema due to foreign body removal has subsided. Education of parents is important to prevent such accidents in toddlers and young children. Use of upper denture prevents tactile sensation and a foreign body is swallowed undetected. Loss of consciousness, epileptic seizures, deep sleep or alcoholic intoxication are other factors. The first symptom of carcinoma oesophagus may be sudden obstruction from a foreign body such as a piece of meat, fruit or vegetable. Flat objects like coins are held up at the sphincter while others are held in the upper oesophagus just below the sphincter due to poor peristalsis. Foreign bodies which pass the sphincter can be held up at the next narrowing at bronchoaortic constriction or at the cardiac end. Once object passes the oesophagus it is likely to pass per rectum but sometimes it gets obstructed at pylorus, duodenum, terminal ileum, ileocaecal junction, caecum, sigmoid colon or even at the rectum. Size and shape of the object and its nature, sharp or pointed plays an important part in its lodgement in oesophagus or lower down. Discomfort or pain located just above the clavicle on the right or left of trachea. Impacted foreign body in the upper oesophagus compresses posterior wall of trachea causing respiratory obstruction especially in children. In partial obstruction, patient may still be taking normal food with little or no discomfort for a few days. No complacency should be observed and an endoscopic examination performed when history and physical examination strongly suggest a foreign body. Most of the foreign bodies in oesophagus can be removed by oesophagoscopy under general anaesthesia. Both rigid and flexible scopes have been used to remove foreign bodies from the oesophagus. Rigid oesophagoscope, appropriate for the size of patient with proper type of forceps is preferred. Soft (meat pieces without bone, vegetable matter) and blunt objects can be removed with flexible scopes (see Table 70. A hypopharyngeal speculum resembling a laryngoscope with long blade is less traumatic and more convenient to use for foreign bodies lodged near the upper sphincter. Impacted foreign bodies or those with sharp hooks such as partial dentures located above thoracic inlet may require removal through an incision in the neck and opening of cervical oesophagus. For impacted foreign bodies of thoracic oesophagus, chest is opened at the appropriate level. Sometimes a foreign body may be seen protruding from the oesophageal opening in the postcricoid region. It is just the reverse in tracheal foreign bodies because of orientation of vocal cords. Radiolucent foreign bodies may show as an air bubble in cervical oesophagus in X-ray soft tissue lateral view of neck. Failure to see a foreign body on X-ray does not rule it out as small fish bones, pieces of wood or plastics are radiolucent. Barium swallow is avoided as it may spill over into the larynx and thus delay the subsequent endoscopic procedure and also make it more difficult. A disc battery may elude as it may cast a double shadow or stacked coin appearance. Patient should take a normal diet and no purgative should be administrated to hasten the passage of foreign body. Operative interference is required when: (a) Patient complains of pain and tenderness in abdomen. Sharp objects may perforate the oesophageal wall, setting up mediastinitis, pericarditis or empyema. They contain sodium hydroxide, potassium hydroxide and mercury which leaks through them to cause oesophageal injury. Prolonged sojourn at one place causes complications like stricture, perforation, tracheo-oesophageal fistula, mediastinitis and death. It does not relax a stricture or oesophageal ring if foreign body is held due to that. Laser Surgery, Radiofrequency Surgery and Hyperbaric Oxygen Therapy Cryosurgery Radiotherapy in Head and Neck Cancer 74. When given energy, electrons change their orbits away from the nucleus and the atoms are then called "excited" but this excited state of atoms does not last long. The atoms soon release their absorbed energy automatically (spontaneous emission) and return to their original state. If photons are made to strike these excited atoms, the decay of the atoms is accelerated and both the incident and the absorbed photons are released (stimulated emission). Laser energy scatters in the tissues and its penetration deep into the tissues becomes limited. The light is transmitted through the tissue without causing any effect on tissues through which it passed. Argon laser has been used to coagulate retinal vessels without any damage to cornea, lens or the vitreous. Lasers which are reflected or transmitted through the tissue do not cause any effect on tissues. Thus lasers can be used to cut (make incision), coagulate blood vessels or vaporize the tissue. A crater is created due to tissue ablation and vaporization leaving behind only a few flakes of carbon. As the laser light is visible, they do not require a separate aiming beam to focus them. It provides constant stable energy; as the active medium is continuously kept in a stimulated mode. Gives interrupted beam as the active medium is intermittently activated for a short time. Lasers have also been used to do a myringotomy, drilling a hole in incus or malleus for ossicular reconstruction, welding of grafts in tympanoplasty or coagulating membranous posterior semicircular canal in benign paroxysmal positional vertigo and in stapes surgery to make a hole in stapes footplate. Some lasers can be passed through optical fibres and can thus be used through flexible endoscopes, straight or curved tubes to ablate tumours situated in difficult locations in the tracheobronchial tube or nasal crevices or clefts. Disadvantages include high cost in the purchase of equipment and its maintenance, special training in operating with lasers, hazards in the use of laser requiring special precautions, and safety measures and special anaesthesia requirements to avoid fires. Focused beam is used for cutting and decofocussed beam for coagulation or ablation of tissues. Wavelength of laser Selective absorptive property of tissues Ability of laser to pass through flexible optical fibre Mode of delivery (continuous wave mode or pulsed mode) Argon laser. It has been used to create a hole in stapes footplate but requires a drop of blood for its absorption at that site so that it is not reflected by white bone of stapes footplate. It lies in visible spectrum, wavelength 532 nm, properties are similar to Argon laser, absorbed by haemoglobin, can be delivered through optical fibres. Clinically it has been used in stapes surgery, endoscopic sinus surgery to remove polyps or inverted papillomas and vascular lesions, 6. It is power density multiplied by duration of exposure in seconds and measured in joules/cm2. It can pass through clear fluids but is absorbed by pigmented tissue and thus has been used in the eye and urinary bladder. It creates nearly 4 mm zone of necrosis and thermal coagulation both in depth and laterally, therefore useful for coagulation of blood vessels or control bleeding. Clinically it has been used to debulk tracheobronchial and oesophageal lesions for palliation, hereditary hemorrhagic telangiectasia and turbinectomy. Requires a micromanipulator if working through an operating microscope, can be absorbed by water or clear glass. Ordinary glass or lenses of the microscope can also absorb the rays as well as the glasses worn by the operator. Clinically it has been used in laryngeal surgery to excise vocal nodules, polyps, cysts, granulomas or juvenile laryngeal papillomas. It is also used for leukoplakia, T1 lesion of vocal cord or localized lesions of supraepiglottis and infraepiglottis. Transverse cordotomy and endoscopic partial or complete arytenoidectomy can also be done in bilateral abductor paralysis. Plastic surgeons have used it to remove benign and malignant lesions of skin and to vaporize naevi and tattoos. Diode lasers have been used in turbinate reduction, laser-assisted stapedectomy and mucosa-intact tonsillar ablation. All personnel working with lasers, doctors, nurses and technical staff of the operation theatre should be educated about the safe use of lasers and their hazards. All the staff working in the operation theatre should use wavelength-specific glasses. Cuff of the tube should be inflated with methyleneblue-mixed saline and then covered with wet cottonoids. In case cuff is accidently damaged by laser, blue colour will alert the surgeon and the tube can be replaced. Concentration of oxygen to ventilate the patient should be commensurate with oxygenation of patient and should not exceed 40%. In addition to suction tube being used by the surgeon to aspirate blood and secretions, another suction tube should be available to remove smoke and steam created by vaporization of tissues. Smoke may be mutagenic and has also been shown to contain virus particles from tissue vaporization of viral papillomas.

Even if the new drug is approved for marketing depression exercise routine discount anafranil master card, it is still subjected to ongoing monitoring of safety and e ectiveness mood disorder definition purchase 10 mg anafranil overnight delivery. The margin of safety de nes the plasma drug concentrations that are therapeutically e ective and safe and those that are considered toxic unipolar depression definition order generic anafranil. Drug hypersensitivity reactions are characterised by inappropriate immune responses to the presence of a drug depression symptoms sleeping too much purchase anafranil line. However anxiety 7 months pregnant purchase anafranil 25mg without a prescription, di erent tissues and organs are more susceptible at certain times during pregnancy depression va disability rating discount anafranil 75 mg on line. Therefore, some drugs are contraindicated only during certain periods in pregnancy. She develops an acute bacterial sinusitis infection caused by Streptococcus pneumoniae. After visiting her doctor, Ms Wallace is prescribed a 14-day course of oral amoxycillin. In view of her advanced stage of pregnancy she is rather concerned about having to take an antibiotic. Using a suitable clinical drug reference, determine the drug category in pregnancy to which amoxycillin belongs. Dose-ranging studies to nd therapeutically e ective and safe dosages in patients who are at risk of adverse e ects. Describe how genetic polymorphism can affect drug responsiveness at the population level. Outline the ethical considerations and the factors that determine costeffectiveness associated with pharmacogenetics. For some people, standard medicine regimens induce inappropriate drug concentrations at the site of action (due to pharmacokinetic variability) or unsuitable e ects at appropriate drug concentrations (due to pharmacodynamic variability). The clinical consequences of such variability can range from poor e ectiveness of treatment to serious injury, or possibly death, caused by adverse drug reactions. At the population level, responsiveness to a particular medicine is considered to be normally distributed. The level of responsiveness decreases as you move to the left or right of this average value. Pharmacogenetics is a branch of pharmacology established to investigate how genetic variation contributes to variable drug responsiveness. Pharmacogenomics is another term used to describe the study of all the genes that determine drug behaviour. However, the two terms, pharmacogenomics and pharmacogenetics, are now frequently used interchangeably. In this article we provide an overview of pharmacogenetics and some clinical considerations associated with this eld of study. Within the human population, genetic variation causes individuals to express di erent forms of these proteins. It is this type of polymorphism that can lead to di erential responses to medicines. Tailor-made drug therapy Clinically, the presence of these genetic markers can be tested for using a suitable diagnostic procedure and then individualised drug treatment can commence. In this case, the genetic markers are the di erent blood groups, and it is this that determines the type of blood the person receives. Simpler and more convenient diagnostic techniques to detect genetic markers will ensure more widespread testing of the population in clinics and hospitals. A slow acetylator is a non-responder who inactivates the medicine more slowly than the general population, leading to an accumulation of the drug in the blood and possible toxicity. A fast acetylator is a responder who degrades the active drug into its acetylated metabolite e ectively. Some individuals, however, can achieve this too e ectively, ending up with lower than normal blood concentrations of the active drug. Such individuals may require a change in the standard dose regimen for these medicines. In terms of ethnicity, recent studies indicate that for N-acetyltransferase, 60 per cent of Caucasians and 20 per cent of Asians are poor metabolisers. A number of important enzymes are involved in drug metabolism-N-acetyltransferase and some of the cytochrome P450 family of oxidative enzymes. For these enzymes, human populations can be divided into two groups based on their ability to metabolise particular medicines-responders (extensive metabolisers) and nonresponders (poor metabolisers). In this section, some welldocumented examples of this bimodal distribution of drug responsiveness are outlined. If, during therapy, plasma drug concentrations remain high because of an inability to degrade the active drug, non-responders are at risk of developing serious adverse drug reactions. Such individuals may require a reassessment of the dose regimen or choice of medicine in order to avoid toxicity. For the responders, the worst scenario is that the medicine will be less e ective because the plasma concentration is subtherapeutic. Ca eine has been used as a safe phenotyping probe to determine fast and slow acetylators. As indicated above, the ratio of ca eine to its metabolites in the urine indicates to which group a person belongs. For each of these enzymes the population is distributed into responders and nonresponders. Interestingly, the polymorphic states of one isoenzyme have no bearing on that of the other. A narrow margin of safety is associated with some of the medicines a ected by this polymorphism. Over recent times, these companies have become more interested in exploring the genetic status of participants in clinical trials in order to account for variation in drug responsiveness. As a consequence of this approach, problematic drugs can be eliminated from the development process during an early stage, at substantial savings in terms of time and money to the company involved. Poor suxamethonium metabolism e role of acetylcholinesterase as the highly speci c degradative enzyme responsible for the inactivation of the neurotransmitter acetylcholine is covered in Chapter 28. Pseudocholinesterases are important in the breakdown of the neuromuscular blocking agent suxamethonium. About 1 in 2000 of the population shows phenotypic variation for pseudocholinesterase synthesis. Non-responders break down suxamethonium more slowly, and in these individuals such treatment leads to prolonged paralysis of about 24 hours. Paralysis, when it occurs, requires that the person be mechanically ventilated and maintained in deep sedation for the duration of the facilitated respiration. Erythrocyte reactions Individuals who have an inheritable defect in the stability of erythrocytes may be more susceptible to either haemolysis or structural changes in haemoglobin during therapy with a number of common clinical medicines. Drugs such as the sulfonamides, antimalarial agents, some non-steroidal anti-in ammatory drugs and the antimicrobial drug chloramphenicol are known to induce these changes. Another condition that can manifest during drug therapy is porphyria, a disorder of haem synthesis. A haem group is formed in either the liver or bone marrow from the combination of a ferrous ion with a pigment called a porphyrin. In porphyria, haem synthesis is abnormal, resulting in the deposition of porphyrins into body tissues such as the skin. Reactions to mydriatics It is also interesting to note that certain drug e ects are enhanced in individuals with a particular family background. Polymorphism and membrane transporters ere is a great deal of interest in polymorphism associated with a number of membrane transporter systems involved in the movement of drugs into (in ux) and out of (e ux) cells. Such polymorphism may contribute to altered drug distribution, clearance and variable e ects. Some of the medicines mentioned above have a narrow therapeutic index, and are associated with serious adverse e ects. It is hoped that the application of pharmacogenetic screening for polymorphic P-gp transporters prior to medicine administration will reduce the incidence of toxicity. Reactions to corticosteroids Another example involving the eye relates to the use of topical corticosteroid therapy (see Chapter 83). Some individuals with a family history of glaucoma have shown raised intraocular pressure in response to eye drops/ ointments containing corticosteroids. Individuals with such a background should be monitored for this during corticosteroid-based eye therapy. First, once the pharmacogenetic data are collected, there are questions of who is entitled to access the information and how con dentiality is protected. For some people, screening prior to treatment may actually reduce the risk because there will be a lower incidence of serious adverse reactions associated with individualised therapy. Will these individuals be refused insurance or pay a signi cantly higher premium if there is no alternative treatment available Genetic variation in the mechanisms by which medicines act has also been found to a ect the observed responses. Variations in receptor structure Recent studies have shown genetic variation in the programming of receptor structures, which, therefore, a ects the observed responses to medicines. Molecular variants of this receptor show normal binding of agonist drugs but a three- to vefold reduction in the response to agonist activation. Even though there has been, and will be, some uptake of pre-prescription testing for particular treatments, widespread routine pharmacogenetic screening seems unlikely. In order to address the question of pharmacogenetic testing on treatment outcomes, rigorous evaluations in randomised controlled clinical trials are required. In such trials, doctors will need to consider genotypes when making decisions about drug therapy for one group of participants, while in another group, empirical drug treatment is used. Genetic variation contributes to di erences in the structure and function of proteins involved in drug metabolism, receptors and other physiological systems involved in drug responsiveness. Where genetic polymorphism exists, drug responsiveness at the population level is broadly divided into responder and non-responder groups. In terms of drug metabolism, this is expressed as extensive and poor metabolisers respectively. Biological markers can be screened for in diagnostic tests to determine whether a person is a responder or nonresponder. Examples of genetic polymorphism have been determined for a number of enzymes involved in drug metabolism, such as N-acetyltransferase, the cytochrome P450 family, membrane transporters and pseudocholinesterases. Genetic polymorphism also exists in the structure of receptors and the responses to certain clinical medicines. At this time, widespread routine pre-prescription pharmacogenetic testing appears unlikely. The coste ectiveness of such testing depends on the prevalence of the polymorphism being considered, the sensitivity and speci city of the testing, the likelihood that, if left untreated, the condition will result in signi cant mortality or morbidity, and that acting on the pharmacogenetic data leads to signi cant treatment outcomes and/or a reduction in costs. He is severely depressed, and is receiving treatment with the tricyclic antidepressant nortriptyline. His doctor has increased the dose manyfold to 200 mg/day, a dose that is inducing e ects. How would this a ect the metabolism of the neuromuscular blocking agent suxamethonium Which biological marker is screened for, and is it the underexpression or overexpression of this marker that is used to determine the appropriateness of this therapy In what way, if any, will this situation a ect the dose of ibuprofen ordered for Jason Name the ways in which drug distribution is altered by disease and pregnancy, and the consequent effects on drug action. List the ways in which drug metabolism is altered by disease, occupation and diet, and the consequent effects on drug action. Describe the ways in which drug excretion is altered by disease, and the consequent effects on drug action. In Chapters 14 and 15 you were introduced to pharmacokinetics, the study of how the human body processes a drug once it has been administered. There are four stages of pharmacokinetics: drug absorption, distribution, metabolism and excretion. In this way, if the dispensing instructions are followed, the drug should reach the site of action in an appropriate concentration that is both safe and therapeutically e ective. Unfortunately, a number of factors can a ect the drug concentration at the site of action. If the concentration is higher than expected, the drug may exert a stronger, and possibly toxic, e ect. If the concentration is lower than expected, the medicine may not be therapeutically e ective. In Chapter 19 we saw an example of this, where genetic variability can a ect the process of drug metabolism. Disease, diet, occupation and pregnancy are other states that can a ect the e ciency of pharmacokinetic processes and ultimately induce stronger or weaker than expected drug e ects. E ective absorption from the oral route depends on both the chemical properties of the drug and the functional e ciency of the gastrointestinal tract. Parenteral absorption depends on the extent of the blood supply through the tissue where the medicine is injected. An example of this is when a person receives an intramuscular drug injection and participates in vigorous exercise shortly a erwards. Effects of diet e presence of food in the gut around the time of medicine administration can greatly a ect the degree of absorption.

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