If the needle points too much in the direction of the foramen order generic accutane from india acne 3 step, the direc- tion needs to be corrected to be more posterior discount 5mg accutane mastercard acne 4dpo. After placement of the first needle order accutane on line amex skin care 999, the other needles are introduced in the same way. It is possible to The advantage of this approach is that the patient is in the maintain eye contact with the patient in the lateral decubitus supine position with easy access to the airways and eye con- position. Bilateral injections The target point is the middle of the articular pillar in the can be performed. The contralateral and ipsilateral articular pil- articular pillar lars are differentiated by rotating the image intensifier along the longitudinal axis. Prevalence of facet joint pain in chronic spinal pain of cervical, thoracic, and lumbar regions. The orientation of the articular fac- ets of the zygapophyseal joints at the cervical and upper thoracic References region. Percutaneous radiofrequency determinants of neck pain in the general population: results of the neurotomy in the treatment of cervical zygapophysial joint pain: a Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its caution. Management of acute and chronic neck disc nucleus in lower cervical spine under compression and sag- pain, Pain research and clinical management. Treatment of neck pain: injections and stability after sequential capsule resection. An anatomi- frequency procedures for the treatment of spinal pain: a system- cal investigation of the human cervical facet capsule, quantifying atic review of randomized clinical trials. Mechanical evidence of cervical facet capsule injury during whip- Radiofrequency denervation for neck and back pain: a systematic lash: a cadaveric study using combined shear, compression, and review within the framework of the cochrane collaboration back extension loading. Factors predicting success Percutaneous radio-frequency neurotomy for chronic cer- and failure for cervical facet radiofrequency denervation: a multi- vical zygapophyseal-joint pain. Ultrasound-guided cervical spine injections: ultra- Headache Disorders, 3rd edition (beta version). Evidence-based interventional pain medicine accord- Transient tetraplegia after cervical facet joint injection for chronic ing to clinical diagnoses: cervicogenic headache. Verrills P, Mitchell B, Vivian D, Nowesenitz G, Lovell B, Mekhail N, Van Zundert J. The incidence of intravascular penetration in medial medicine according to clinical diagnoses: cervical facet pain. Randomised controlled trial of cervical articular corticosteroids for chronic pain in the cervical zygapophy- radiofrequency lesions as a treatment for cervicogenic headache sial joints. Even though headaches are ologic mechanisms postulated [6], the intractable headache one of the most frequent symptoms encountered in general seems to lack a peripheral pathology [7]. It may be asso- and neurological practice, only 3 % of the general popula- ciated with a central sensitization phenomenon and varia- tion experience chronic headaches on more than 15 days per tions in the levels of glutamate, dopamine, or magnesium month [2]. Manipulation of the pathways involv- by the International Headache Society, a significant number ing central neurotransmitters seems to be the basis for the of patients suffer from pain that is not responsive to routine effectiveness of infusion therapies. Approximately 10 % of all headaches for which patients seek treatment are labeled by practitioners as intractable Common Intravenous Medications headache, a term for a headache that is difficult to treat, for Intractable Headaches relieve, or cure [4, 5]. It has a half-life of approximately • Treatment failures (which and how many treatments a 10–14 h and is primarily used for intractable migraine and patient has failed in the past) cluster headaches. Pretreatment with an antiemetic is warranted University of Chicago Medical Center, 5841 S. Ach X Cholinergic neurotransmission may A marker for reflex activation of the be disturbed during migraine attacks parasympathetic nervous system? Physiological markers Vasodilatation X Intracranial and extracranial vessels Distension of blood vessel walls sometimes dilate Vasoconstriction X? Observed in prodromal phase Ischemia Hormonal markers Progesterone estrogen X X Migraine frequency higher in females, like Mechanism not known, perhaps release of to menstrual cycle, puberty, pregnancy, prostaglandins menopause Various Genetic “defects” in some forms Not related directly to pain generators? Several studies have 14 Intravenous Therapies for Intractable Headache 95 Table 14. Thereafter may use metoclopramide 10 mg oral tablets every 8 h prn for nausea not to exceed 30 mg per 24 h 4. If significant nausea, leg cramping, or vomiting occurs, decrease the infusion to 21–30 ml/h 6. Outside the nervous system, through a modulatory col to treat refractory headache. Used in the clinic Valproate setting for the treatment of severe headache, intravenous valproate is relatively safe. It does not produce cardiovas- Sodium valproate is effective in its oral form for migraine pro- cular effects or deep sedation. Several common protocols for using valproate sodium ulates nitric oxide production, recently implicated in the in the treatment of refractory headache are summarized in pathophysiology of headache [29]. Patients were given intermittent boluses of 20 mg Magnesium propofol every 10 min to a total dose of 120 mg. Other stud- ies have described intermittent subanesthetic doses (20– Magnesium, the second most abundant intracellular cation, 30 mg boluses) of propofol every 3–5 min to an average dose is frequently decreased in patients with migraine, espe- of 233±74 mg over 20–30 min. Pain decreased 60 % in all cially when the headache is associated with an aura [24 ]. In one Magnesium also maintains calcium homeostasis by bind- randomized, double-blind, controlled study, patients who ing to the N-methyl-d-aspartate glutamate receptors. It received 40 mcg/kg/min of a propofol infusion over 20 min modulates the release of substance P and the production showed a statistically significant but not clinically meaning- of nitric oxide [10], processes known to be involved in the ful reduction in headache-related disability 30 days after the pathophysiology of migraine headache. Oral magnesium in infusion but no reduction in pain or analgesic use during doses of 400 mg/day reduced the frequency of headaches in the 30-day follow-up [29]. Intravenous from small open-label studies and case reports, propofol administration of 1 g magnesium rendered 80 % of head- may remain a drug for the abortive treatment of refractory ache patients pain-free 15 min after infusion [26]. Lidocaine has been used safely and effectively in patients Since magnesium is a potent vasodilator, concomitant with trigeminal neuralgia, diabetic neuropathy, fibromyalgia, administration with intravenous metoclopramide may cancer pain resistant to opioid treatment, and pain from spinal worsen the therapeutic outcome. Several case reports advocate also can be administered for reversible cerebral vasocon- the efficacy of systemic lidocaine in short-lasting unilateral striction syndrome together with calcium channel blockers neuralgiform headache attacks with conjunctival injec- and steroids [28]. In an inpatient setting at doses of 1 mg/min for Consultation 4 h followed by 2 mg/min for a mean of 8. In a Day of procedure series of 71 patients, intravenous lidocaine effectively less- Assess the patient for fasting and alertness ened the pain associated with severe headache, chronic daily Determine effects of previous infusion, if any on headache, transformed migraine, and medication overuse Pain reduction Duration of effects headache in 90 % of subjects. This effect was maintained at Patient function after infusion 1-month follow-up, and 76 % of patients reported lessening Decrease in use of pain medication since infusion in severity of headache [34, 35]. The most common compli- Verify that patient has companion to accompany patient home cations were nausea, vomiting, hallucinations, tachycardia, Obtain signed consent on the consent form or tremors, which resolved with dose reduction. Our protocol for outpatient lidocaine infusions is Heart rate described in Table 14. In an open-label study, 247 patients with vari- tors, the nitric oxide pathway, and m-opioid receptors [37 ]. It of intractable migraine was reduced by more than 50 % in has been extensively studied as a therapeutic agent in com- 93 % of 162 patients [40, 41].

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Joint arthroscopies are usually component and another for the femoral compo- performed as outpatient procedures order accutane overnight delivery acne medication oral. Minimally invasive typical patient undergoing knee arthroscopy is ofen techniques can reduce hospitalization to 24 h or less order accutane 10 mg online acne 2015. Hip Arthroscopy Intraoperative Management In recent years purchase accutane 40 mg with visa acne active, hip arthroscopy has increased in A bloodless feld greatly facilitates arthroscopic sur- popularity as a minimally invasive alternative to gery. Fortunately, knee surgery lends itself to the open arthrotomy for a variety of surgical indications use of a pneumatic tourniquet. However, T ere is a 3% incidence of hip dislocation following for ambulatory surgery, time to discharge following primary hip arthroplasty and a 20% incidence fol- neuraxial anesthesia may be prolonged compared lowing total hip revision arthroplasty. Successful outpatient recovery depends on early Extremes of hip fexion, internal rotation, and adduc- ambulation, adequate pain relief, and minimal nau- tion increase the risk of dislocation. Techniques that avoid large doses may be corrected with closed reduction facilitated by of systemic opioids have obvious appeal. Temporary paraly- Intraarticular local anesthetics (bupivacaine or ropi- sis can be provided by succinylcholine, if necessary, vacaine) usually provide satisfactory analgesia for to facilitate the reduction when the hip musculature several hours postoperatively. Successful reduction should 9 as opioids, clonidine, ketorolac, epinephrine, be confrmed radiologically prior to the patient’s and neostigmine when added to local anesthetic emergence. Cooperative patients usually tolerate a neuraxial anesthetic Preoperative Considerations technique with intravenous sedation. Anesthetic management and 10 itates early physical rehabilitation to maximize postoperative analgesia should accommodate and postoperative range of motion and prevent joint facilitate the accelerated recovery schedule. It is impor- or continuous peripheral nerve blocks, alone or tant to balance pain control with the need for an alert in combination, can provide target-specifc pain and cooperative patient during physical therapy. In ran- Epidural analgesia is useful in bilateral knee replace- domized clinical trials, continuous peripheral ments. For unilateral knee replacement, lumbar nerve block catheters with subsequent perineu- epidural and femoral perineural catheters provide ral local anesthetic infusions have been shown equivalent analgesia while femoral perineural to decrease time to meet discharge criteria for catheters produce fewer side efects (eg, pruritus, total knee arthroplasty. The management of peri- nausea and vomiting, urinary retention, or ortho- neural catheters takes a hands-on team approach static lightheadedness). Preoperative placement in and can be incorporated into integrated clinical a “block room” can prevent operating room delays pathways involving surgery, nursing, and physi- and ensure that patients receive this benefcial anal- cal therapy. Tese procedures are performed either in a sitting (“beach chair”) or, less commonly, the lateral decu- bitus position. If chial plexus block is the preferred regional anesthetic a surgeon requests controlled hypotension, an arte- technique. Multiple approaches can be used to anes- rial catheter for invasive blood pressure monitoring thetize the brachial plexus for distal upper extrem- is recommended, and the transducer should be ity surgery (see Chapter 46). Selection of brachial positioned at leasThat the level of the heart or, prefer- plexus block technique should take into account the ably, the brainstem (external meatus of the ear). Continuous peripheral 11 ultrasound or electrical stimulation is ideally nerve blocks may be appropriate for inpatient and suited for shoulder procedures. The supraclavicular select outpatient procedures to extend the duration approach also can be used. Even when general anes- of analgesia further into the postoperative period thesia is employed, an interscalene block can supple- or facilitate physical therapy. Brachial plexus blocks ment anesthesia and provide efective postoperative do not anesthetize the intercostobrachial nerve dis- analgesia. Intense muscle relaxation is usually tribution (arising from the dorsal rami of T1 and required for major shoulder surgery during general sometimes T2); hence, subcutaneous infltration anesthesia, particularly when not combined with a of local anesthetic may be required for procedures brachial plexus block. Preoperative insertion of an indwelling peri- Anesthetic considerations for distal upper neural catheter with subsequent infusion of a extremity surgery should include patient position- dilute local anesthetic infusion solution allows ing and use of a pneumatic tourniquet. Most proce- postoperative analgesia for 48–72 h with most dures can be performed with the patient supine; the fxed-reservoir disposable pumps following operative arm abducted 90° and resting on a hand arthroscopic or open shoulder operations (see table; and the operating room table rotated 90° to Chapter 46). Alternatively, surgeons may insert a position the operative arm in the center of the room. Because patients are ofen scheduled for has been associated with postarthroscopic gleno- same-day discharge, perioperative management humeral chondrolysis in retrospective human and should focus on ensuring rapid emergence and pre- prospective animal studies and is not currently rec- venting severe postoperative pain and nausea (see ommended. The patient has operations of the hand (eg, carpal tunnel release) of received chemotherapy over the last 2 months short duration may be performed with local infltra- with multiple drugs, including doxorubicin. Hemipelvectomy involves radical resection Jehovah’s Witnesses, a fellowship of more than that can lead to massive blood loss. This is particu- 1 million Americans, object to the administration of larly true for large tumors removed using the more blood for any indication. Invasive arterial blood their interpretation of the Bible (“to keep abstain- pressure and central venous pressure monitors ing from. Techniques that minimize intra- obliged to honor the principle of autonomy, which operative blood loss (eg, controlled hypotension, upholds that patients have final authority over aprotinin) should be considered. Witnesses typically sign a Witness, the management of life-threatening ane- waiver releasing physicians of liability for any con- mia (Hb <5 g/dL) may be improved by monitor- sequences of blood refusal. Witnesses abstain from blood and blood products (eg, packed red blood cells, fresh frozen What physiological effects result from severe plasma, platelets) but not non–blood-containing anemia? They accept crystalloids, hetastarch, and Assuming the maintenance of normovolemia dextran replacement solutions. Witnesses often and the absence of preexisting major end-organ view albumin, erythropoietin (because of the use dysfunction, most patients tolerate severe anemia of albumin), immune globulins, and hemophiliac surprisingly well. Decreased blood viscosity and preparations as a gray area that requires a personal vasodilation lower systemic vascular resistance decision by the believer. Augmentation of stroke volume increases cardiac output, allowing arterial Do they allow the use of autologous blood? Coronary and cerebral blood flows removed from the body should be discarded (“You increase in the absence of coronary artery disease should pour it out upon the ground as water,” and carotid artery stenosis. Thus, the oxygen saturation reflects an increase in tissue oxy- usual practice of autologous preoperative collec- gen extraction. Techniques result of dilutional coagulopathy may accompany of acute normovolemic hemodilution and intraop- extreme degrees of anemia. For example, up to 4 units of blood could be This anthracycline chemotherapeutic agent drawn from the patient immediately before surgery has well-recognized cardiac side effects, rang- and kept in anticoagulant-containing bags that ing from transient arrhythmias and electrocar- maintain a constant link to the patient’s body. The other important toxicity of doxorubicin is between lower extremity continuous peripheral myelosuppression manifesting as thrombocytope- nerve blocks and patient falls afer knee and hip nia, leukopenia, and anemia. Transfusion- following head injuries, likely because of related acute lung injury is the leading cause of transfusion-related death. Cardiac output succinylcholine administration is likely declines by up to 50% within 30 minutes to produce potentially lethal elevation in response to massive vasoconstriction, of serum potassium levels. All aspects of trauma care, A i r w a y from that provided at the scene, through transport, Increasingly, emergency medical technician– resuscitation, surgery, intensive care, and rehabili- paramedics and fight nurses are trained to intu- tation, must be coordinated if the patient is to have bate patients in the prehospital environment.

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Precise identifcation of various Hallmarks Characteristic facial features with hirsutism order accutane 5 mg with visa acne yahoo, chromosomal abnormalities generic accutane 5mg fast delivery acne infection. Further delineation of the dup(3q) Syndrome these two conditions are etiologically and pheno- syndrome discount 5mg accutane with amex acne xarelto. Partial trisomy 3q in a child with sacrococcygeal teratoma and Cornelia de Lange syndrome phe- notype. Presentation Duplication 3q syndrome partially overlaps with the Brachmann-de Lange phenotype. Convulsions, eye, palate, renal, and cardiac anomalies are more frequent in duplication 3q syndrome, whereas limb defciencies, hirsut- ism, and synophrys are more characteristic of Cornelia de Lange syndrome. Spine Pterygium colli with short or webbed neck, chest wall deformities, hypoplastic frst ribs, absent twelfth ribs, and short sternum. Autosomal recessive Peters anomaly, typical facial appearance, failure to thrive, hydro- cephalus, and other anomalies: further delineation of the Krause- Background Peters [1] in 1906 described in the German Kivlin syndrome. Etiology The condition is caused by biallelic mutations in the beta-1,3-galactosyltransferase-like gene [4]. Presentation Growth defciency is present prenatally and postnatal defcient limb growth occurs that leads to dwarfsm. Upper extremity Brachydactyly that may be tapering [5] and affect all digits and small fnger clinodactyly are the most common. Craniofacial A round face, thin upper lip, and hypoplastic columella of the inner ear are common fndings. Hallmarks Craniofacial Sebaceous nevi, ipsilateral abnor- malities of the central nervous system, ocular anomalies, and References skeletal defects. Linear nevus sebaceus with convulsions chiatrist who in 1957 described a case of “new phacomatosis” and mental retardation. Johns Hop- lateral ocular abnormalities including coloboma of the eye- kins University. Skeletal changes in epider- patients with linear nevus sebaceous of the face along with mal nevus syndrome: does focal bone disease harbor clues concern- epilepsy and mental retardation [2]. Infammatory linear verrucous epidermal nevus of the digits treated with surgical excision and skin grafting. Dandy-Walker malformation associated with hemimegalencephaly in the sebaceous nevus syndrome. Presentation The condition is primarily a neurocutane- ous disorder that usually presents at birth and affects both genders equally. The patient has linear verrucous epider- mal nevus or nevi following the lines of Blaschko, which are pruritic plaques, often present on the face but can be noted on the limb or trunk. Developmental delay and intel- lectual disability may be present, although intelligence may be normal [4]. General musculoskeletal There is diffuse osteopenia that is associated with hypophosphatemic rickets and radiographic and histopathologic fndings of fbrous dysplasia. Upper extremity In addition to the nevi in the upper extrem- ity and digits [6] the patient may have thumb polydactyly, congenital amputation, syndactyly, and clinodactyly. Lower extremity Congenital dislocation of the hip, genu recurvatum, and congenital amputation may be encountered. Syndactyly 28 Syndactyly (from the Greek: syn = together, dactylos = digit) bundles. These must be released if subsequent contracture is or digital webbing is one of the two most common congenital to be avoided following separation (. This fusion of digits usually presents as an isolated anomaly, but it synostosis typically occurs distally but may occur anywhere is also frequently encountered in association with other soft along the longitudinal axis of the digital ray. Because the tissue and osseous anomalies of the hand and malformations genetically determined length of individual digits may be dif- of other organ systems including many syndromes. The presence of weeks of gestation, due to failure of the “programmed cell such deformities will affect surgical timing (. Some pediatricians and clinical geneticists continue to coalition at any level, most commonly the distal phalanx, use this historical classifcation. In order of decreasing frequency, Surgeons prefer this classifcation because their focus is syndactyly affects most often the third web space, or the primarily on the abnormal anatomy encountered and the lo- middle and ring fngers, followed by the ring and small fn- gistics of proper separation. In a simple complete or incom- gers, index and middle fngers and lastly the thumb and in- plete webbing abnormal fbrous bands are found to originate dex fngers. The condition can be inherited as an autosomal both above (dorsal) and below (palmar) the neurovascular dominant pattern with incomplete penetrance. Surgeons prefer a system that des- polydactyly, bizarre phalangeal confgurations, and abnormal growth ignates four types of digital webbing. This anomaly is part of the amniotic constriction band which among surgeons is commonly called the constric- involvement is common. The involved digits are fused together as a result of in utero The skin in syndactyly is invariably defcient, especially infammation and scar formation precipitated by the amni- in the region of the normal commissure. The fenestrations are cumference of two digits held together and comparing it with the incomplete separation of the webbing (. It the sum of the circumferences of the individual digits can occurs in severe cases that are in utero amputated and the demonstrate the lack of skin [4–6] (. Within these hands, terconnections are present in webbed digits in the mid axial there are always remnants of the web space commissures line and extend across the interdigital space at the level of that present as proximal dorsal-to-palmar skin or sinus tract. These bands may incor- Amniotic constriction band and associated acrosyndactyly porate Cleland ligaments dorsal to the neurovascular bundle develop often later than the frst trimester and are not geneti- and Grayson ligaments palmar to the neurovascular bundle cally predisposed. Digital nerves and arteries may have a wide variety of branching patterns within a web space and distal branching is common for both [7]. Skin grafts or additional skin is needed web space shows an hourglass confguration, which has a dorsal-to-pal- in all but the most incomplete syndactyly corrections. They originate along the sides of the digits above and below the neu- rovascular bundles from the same fbers, which constitute the dorsal Cleland and the palmar Grayson ligaments in the normal well-differ- entiated digit. The level of these sinuses is always distal to the level of the Epidermal nevus (Linear sebaceous nevus) syndrome normal commissure. Congenital amputation or loss of digits distal to Bloch-Sulzberger (Incontinentia Pigmenti) syndrome these rings is common. In a much more comprehensive study Upton [7] described Etiology The condition is due to autosomal dominant muta- three basic types (. Minor subcategories have been added but is thought to be related to an uncoordinated differentiation the three basic groups remain as they have great bearing upon of mesenchyme at the time of skeletal development in both clinical decision-making. Often there is skeletal dys- abnormalities play a signifcant role in the continued malfor- plasia of the shoulder and occasionally of the elbow joints, mation with growth both prenatal and postnatal. The gle- nohumeral joint is hypoplastic and with time the humeral head Presentation Intelligence and cognitive development may becomes too large for the glenoid and subluxes anteriorly. In be challenged in many of these children but a large proportion our series of 150 Apert patients we have seen a humeroulnar of these patients have normal intelligence. Proximal radioulnar synostosis does occur therefore is not a consistent feature of the syndrome and in the slightly more frequently and restricts forearm rotation in these past it was reported to be much more frequent probably as a children who always seem to compensate with hypermobility result of delayed diagnosis of neurologic defcits particularly of the wrist and adaptive body positioning. Patients who nar joint is normal but carpal coalition is common, particularly have craniectomies early in life may have better intelligence. At birth all these children have a noticeable cranial malforma- The metacarpals are the least affected except in the thumb, tion, midface retrusion with a parrot beak nose, and deformi- which are universally short in comparison to those of children ties of the hands and to a lesser extent the feet (.

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These drugs are This in turn influences diffusibility because: also referred to as non-polar 5mg accutane for sale acne gibson. Permanently ionised drugs Quantifying the degree of ionisation helps to express the profound effect of environmental pH order accutane acne en la espalda. Recall that when the Drugs that are permanently ionised contain groups that pHoftheenvironmentisthesameasthepKaofadrugwithin dissociate so strongly that they remain ionised over the it discount accutane 40 mg amex acne attack, then the ratio of un-ionised to ionised molecules is 1:1. Such compounds are termed polar, But for every unit by which pH is changed, the ratio of un- for their groups are either negatively charged (acidic, e. This is a disadvantage largest and most numerous in jejunal epithelium, and fil- with heparin, which the gut does not absorb, so that it is tration allows for rapid equilibration of concentrations given parenterally. Conversely, heparin is a useful anticoag- and consequently of osmotic pressures across the mucosa. The following are particular examples of the relevance of Filtration seems to play at most a minor role in drug trans- drug passage across membranes. The capillaries of the cerebral circulation differ from those in most other Carrier-mediated transport parts of the body in that they lack the filtration channels between endothelial cells through which substances in The membranes of many cells incorporate carrier-mediated the blood normally gain access to the extracellular fluid. Drugs that bear some Compounds that are lipid insoluble do not cross it readily, structural resemblance to natural constituents of the body e. Other, energy- Conversely lipid-soluble substances enter brain tissue with requiring processes move substrates into or out of cells ease; thus diazepam (lipid soluble) given intravenously is ef- against a concentration gradient very effectively, i. Maternal blood bathes the chorionic villi, which consist of a layer of trophoblastic cells that enclose fetal capillaries. Their large surface area and the high pla- In the body, drug molecules reach their sites of action after cental blood flow (500 mL/min) are essential for gas ex- crossing cell membranes and cells, and many are metabo- change, uptake of nutrients and elimination of waste lised in the process. Thus a lipid barrier separates the fetal and mater- changes take place is subject to important influences called nal bloodstreams, allowing the passage of lipid-soluble the order of reaction or process. In biology generally, two or- substances but excluding water-soluble compounds, espe- ders of such reactions are recognised, and are summarised cially those with a molecular weight exceeding 600. First-order (exponential) processes In the majority of instances, the rates at which absorption, Filtration distribution, metabolism and excretion of a drug occur are Aqueous channels in the tight junctions between adjacent directly proportional to its concentration in the body. In other words, at high concentrations there are tinues to drink, the blood alcohol concentration rises dis- more opportunities for crowded molecules to interact with proportionately, for the rate of metabolism remains the one another or to cross cell membranes than at low, same, as alcohol shows zero-order kinetics. Consider a man of average size who of reaction is proportional to the concentration of partici- drinks about half (375 mL) a standard bottle of whisky pating molecules are first-order processes. The cur- tabolism were subject to first-order kinetics, with a t½of 1 h rent chapter later describes how the rate of elimination throughout the whole range of social consumption, the of a drug from the plasma falls as the concentration in subject would halve his blood alcohol concentration each plasma falls, and the time for any plasma concentration hour (see Fig. It is easy to calculate that, when he to fall by 50% (t½, the plasma half-life) is always the drives his car to work at 08. Thus, it becomes possible to quote a constant value he has a negligible blood alcohol concentration (less than for the t½ of the drug. This occurs because rate and 1 mg/dL) though, no doubt, a hangover might reduce his concentration are in proportion, i. BuThat these high concentrations, alcohol is in fact sub- Knowing that first-order conditions apply to a drug ject to zero-order kinetics and so, metabolising about allows accurate calculations that depend on its t½, i. The subject has an accident on his way to work and is breathalysed despite Zero-order processes (saturation his indignant protests that he last touched a drop before midnight. Banned from the road, on his train journey kinetics) to work he will have leisure to reflect on the difference be- As the amount of drug in the body rises, metabolic reac- tween first-order and zero-order kinetics (though this is tions or processes that have limited capacity become satu- unlikely! The example above describes an imagined maximum amounThat which it stays constant, e. Phe- limited activity of an enzyme, and any further increase in nytoin, at low dose, exhibits a first-order elimination pro- rate is impossible despite an increase in the dose of drug. In practice, proaches and reaches saturation, the process becoming enzyme-mediated metabolic reactions are the most likely constant and zero order. While the dosing rate can be in- to show rate limitation because the amount of enzyme pre- creased, the metabolism rate cannot, and the plasma sent is finite and can become saturated. Above this concentration the main enzyme (alcohol dehydrogenase) that converts the alcohol into acetalde- hyde approaches and then reaches saturation, at which 1 1 1 1 t /2 t /2 t /2 t /2 point alcohol metabolism cannot proceed any faster than Fig. Note: because the rate of a reaction is constant when it is zero order, it is (the distribution phase, see text, is not shown). As elimination is dose independent, but as zero order is approached, with increasing dose a first-order process, the time for any concentration point to fall the kinetics alter, and thus are called dose dependent. Salicylate metabolism also exhibits satura- constant dosing tion kinetics buThat high therapeutic doses. Clearly saturation kinetics is a significant factor in delay of recovery With a constant rate infusion, the amount of drug in the from drug overdose, e. Whenadrugissubjecttofirst- is reached at which the rate of administration to the body is ½ order kinetics, the t is a constant characteristic, i. The plasma concentration is then on a pla- range (accepting that there will be variation in t between in- teau, and the drug effect is stable. But if the rate of a process is smooth changes in plasma concentration that result from not directly proportional to plasma concentration, then the a constant intravenous infusion. Consequently, no single value for regularly spaced oral or intravenous doses will result in ½ t describes overall elimination when a drug exhibits zero- plasma concentrations that fluctuate between peaks and ½ order kinetics. In fact, t decreasesasplasmaconcentration troughs, but in time all of the peaks will be of equal height ½ falls and the calculations on elimination and dosing that and all of the troughs will be of equal depth; this is also are so easy with first-order elimination (see below) become called a steady-state concentration, as the mean concentra- tion is constant. Zero-order absorption processes apply to iron, to depot intramuscular formulations and to drug implants, e. There is then a sharp drop commences and plasma concentration rises to reach a steady state (plateau) in about 5 Â t½ periods. If the than the original steady state; the process takes another 5 Â t ½ elimination processes are first order, the time taken for periods. Note that the drug is virtually eliminated from and the plasma concentration falls to virtually zero in the plasma in five t½ periods. The t½is the one pharmacokinetic value of a drug that 6The peaks and troughs can be of practical importance with drugs of low it is most useful to know. Benzylpenicillin 30 min Amoxicillin 1 h When a drug is given at a constant rate (continuous or Paracetamol 2 h repeated administration), the time to reach steady state depends only on the t and, for all practical Midazolam 3 h ½ purposes, after 5 Â t½ periods the amount of drug in Tolbutamide 6 h the body is constant and the plasma concentration is at a plateau (a–b in Fig. Atenolol 7 h Dosulepin 25 h Change in plasma concentration with Diazepam 40 h change or cessation of dosing Piroxicam 45 h The same principle holds for change from any steady-state Ethosuximide 54 h plasma concentration to a new steady state brought about by increase or decrease in the rate of drug administration. Provided the kinetics remain first order, increasing or de- Biological effect t is the time in which the biological ef- ½ creasing the rate of drug administration (b and c in fect of a drug declines by one-half. Sometimes the biological effect t ½ tion (100%), discontinuing the dose (d in Fig. Note that the difference between the rate of drug ad- ministration (input) and the rate of elimination (output) determines the actual level of any steady-state plasma con- Therapeutic drug monitoring centration (as opposed to the time taken to reach it). If drug Patients differ greatly in the dose of drug required to elimination remains constant and administration increases achieve the same response. The dose of warfarin that by 50%, in time the plasma concentration will reach a new maintains a therapeutic concentration may vary as much steady-state concentration, which will be 50% greater than as five-fold between individuals.