I. Moff. Northwest Nazarene University.

However generic top avana 80 mg otc, amphetamine has tic posture in which the back is arched and only the effects beyond displacement of catecholamines; these in- back of the head and the heels are touching the surface clude inhibition of neuronal amine uptake best 80 mg top avana, direct stimula- on which the victim is lying generic 80mg top avana with amex. Under the influence of strychnine cheap top avana 80 mg with amex, catecholamine action at certain subtypes of adrenocep- all sensory stimuli produce exaggerated responses generic top avana 80mg line. Interestingly, primary therapeutic consideration after strychnine poi- none of these actions explains the therapeutic benefit of soning is to prevent convulsions, which may be fatal. Diazepam and clonazepam (see Chapter 33) appear to be moderately effective in preventing strychnine con- Clinical Uses vulsions, and either of these is the agent of choice. Barbiturates are often used to treat overdoses of all of The therapeutic indications for the psychomotor stimu- the analeptic stimulants. This is generally a childhood disease characterized by PSYCHOMOTOR STIMULANTS hyperactivity, inability to concentrate, and impulsive be- havior. Amphetamines and the more extensively used methylphenidate paradoxically are quite effective in Pharmacokinetics calming a large proportion of children with this disor- Many psychomotor stimulants possess activities similar der. Pemoline (Cylert) is also used in the treatment of to those of amphetamine and have been discussed pre- attention deficit disorder with hyperkinetic behavior. Of primary importance to our The mechanism by which these compounds are effec- discussion of the psychomotor stimulants are ampheta- tive in this disorder is not known. Drugs that influ- metabolize the amphetamines, a considerable portion ence the central action of adrenomimetic amines re- 29 Central Nervous System Stimulants 351 markably affect narcolepsy. While mine compound whose mechanism of action is not the xanthines have legitimate therapeutic uses, by far known but that has been shown to be successful in the the greatest public exposure to them is in xanthine- treatment of narcolepsy. However, amphetamine and containing beverages, including coffee, tea, cocoa, and methylphenidate are still considered among the drugs cola drinks. It is primarily for this reason that xanthines are other centrally acting adrenomimetics has been in the listed as CNS stimulants in this text. Although the amphetamines have a significant anorexic effect, Chemistry and Pharmacokinetics tolerance to this action develops within a few weeks. In addition, insomnia restricted their use during the latter Three xanthines are pharmacologically important: caf- part of the day. All three alka- opment of tolerance and potential for drug abuse have loids, which occur naturally in certain plants, are widely convinced much of the medical community that the use consumed in the form of beverages (infusions or decoc- of amphetamines in weight control is inappropriate. Coffee primarily con- Fenfluramine (Pondimin) and phentermine (Adipex- tains caffeine (about 100–150 mg per average cup); tea P, Fastin) are anorexigenic drugs that produce depres- contains caffeine (30–40 mg per cup) and theophylline; sion of the CNS and at one time were used (Fen-phen) and cocoa contains caffeine (15–18 mg per cup) and in the treatment of obesity. The CNS stimulation associated with these beverages is predomi- Adverse Effects nantly due to the caffeine. The xanthines are readily absorbed by the oral and The acute effects of psychomotor stimulant overdoses rectal routes. Although these agents can be adminis- are related to their CNS stimulant properties and may tered by injection (aminophylline is a soluble salt of include euphoria, dizziness, tremor, irritability, and in- theophylline), intravascular administration is indicated somnia. At higher doses, convulsions and coma may en- only in status asthmaticus and apnea in premature in- sue. Intramuscular injection generally produces con- headache, palpitation, cardiac arrhythmias, anginal siderable pain at the injection site. Dextro- The compounds are extensively metabolized, prima- amphetamine produces somewhat less cardiac stimula- rily to uric acid derivatives. These agents produce addiction, including psycholog- Mechanism of Action ical dependence, tolerance, and physical dependence. The mechanism of action of methylxanthine-induced Psychic dependence also has been seen following high stimulation of the CNS has been the subject of much in- doses of methylphenidate. The abstinence syndrome seen vestigation, and at least two other possible mechanisms after abrupt discontinuation of amphetamines is neither of action of the methylxanthines have been suggested. With the to act as antagonists of the naturally occurring com- amphetamines, the abstinence syndrome consists prima- pound adenosine, a substance that can inhibit both neu- rily of prolonged sleep, fatigue, and extreme hunger (hy- ronal activity and behavior through direct postsynaptic perphagia). These symptoms may be accompanied by action on neurons and through indirect action involving profound and long-lasting depression. Thus, as an equilibrium-competitive antagonist of adenosine, the methylxanthines may pro- XANTHINES duce excitation either by direct blockade of inhibitory The compounds known as xanthines, methylxanthines, effects of adenosine at the neuron or by an antagonism or xanthine derivatives constitute a particularly inter- of the presynaptic inhibitory effect of adenosine on the esting class of drugs. Caffeine can compete for binding at the Xanthines (usually caffeine) are frequently combined benzodiazepine site and would therefore be expected to with aspirin in the treatment of headaches.

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Respiratory complications may be caused by inhalation of smoke and toxic chemicals buy 80mg top avana visa, and circulatory problems may result from loss of fluids and Anterior Posterior electrolytes generic 80 mg top avana mastercard. Tanning requires the skin to protect it- Box 6-3 • Health Maintenance The Dark Side of the SunThe Dark Side of the Sun he three most common forms of skin cancer—basal cell selves and possibly cancerous generic top avana 80mg without prescription. UV rays following: also cause premature aging of the skin buy top avana 80 mg line, including wrinkling cheap 80mg top avana with mastercard, discoloration (“age spots” or “liver spots”), and a change in ◗ Limit exposure during midday when the level of UV radia- texture most often referred to as “leathery skin. Muscle tissue and nervous tissue, which stop di- skin may become transparent and lose its elasticity, the ef- viding early in life, generally do not restore themselves, fect of which is sometimes called “parchment skin. However, there may When muscle and nervous tissues are injured, they are be localized areas of extra pigmentation in the skin with the generally replaced by connective tissue. The texture of the hair changes as the hair sive growth of new connective tissue, which develops shaft becomes less dense, and hair, like the skin, be- from within the wound. The sweat glands decrease in number, so there is less After the upper layer of epithelium has regenerated, output of perspiration and lowered ability to withstand the scab is released. The fingernails sue is strong but is not as flexible as normal tissue and may flake, become brittle, or develop ridges, and toenails does not function like the tissue it replaces. Careful hand washing with soap ◗ Nutrition—A complete and balanced diet will provide and water, with attention to the under-nail areas, is a sim- the nutrients needed for cell regeneration. The person with atopic dermati- known, but there is sometimes a hereditary pattern, and an tis may also be subject to allergic disorders, such as hay immune disorder may be involved. Exposure to sunlight predisposes to devel- opment of skin cancer, which, in the United States, is most common among people who have fair skin and who live in the Southwest, where exposure to the sun is con- sistent and may be intense. A predisposing factor for melanoma is severe, blistering sunburn, although these cancers can ap- pear in areas not sun-exposed, such as the soles of the feet, Figure 6-10 Atopic dermatitis (eczema). Usually benign, warts have been associated with cancer, especially in the case of genital warts and cancer Acne (AK-ne) is a disease of the sebaceous (oil) glands of the cervix (neck of the uterus). The common type, called acne vulgaris (vul-GA-ris), is found most often in Fungal Infections Fungi are non-green, plantlike mi- people between the ages of 14 and 25 years. Acne is usually most severe at known as tinea or ringworm, may appear on the face, body, adolescence, when certain endocrine glands that control scalp, hands, or feet (Fig. Fungal Impetigo Impetigo (im-peh-TI-go) is an acute conta- infections of the nails commonly result from wearing false gious disease of staphylococcal or streptococcal origin nails or acrylic nails, as fungal growth is promoted by the that may be serious enough to cause death in newborn in- moisture that accumulates under the artificial nails. Viral Infections One virus that involves the skin is herpes (HER-peze) simplex virus, which causes the for- mation of watery vesicles (cold sores, fever blisters) on the skin and mucous membranes. SLE is more plications of the drug minoxidil (used as an oral medica- prevalent in women than in men and has a higher inci- tion to control blood pressure) have produced growth of dence among Asians and blacks than in other popula- hair in this type of baldness. Internal organs become involved in a diffuse form of scleroderma called progressive systemic sclerosis Allergy, also known as hypersensitivity, is an unfavorable (PSS). Often the skin is in- Pressure ulcers are skin lesions that appear where the volved in such responses, showing inflammation, rashes, body rests on skin that covers bony projections, such as vesicles, or other forms of eruptions, usually accompa- the spine, heel, elbow, or hip. Poor Urticaria (ur-tih-KA-re-ah), or hives, is an allergic re- general health, malnutrition, age, obesity, and infection action characterized by the temporary appearance of ele- contribute to the development of pressure ulcers. If ignored, they may penetrate the skin and underlying muscle, ex- Autoimmune Disorders An autoimmune disease re- tending even to bone and requiring months to heal. The Pads or mattresses to relieve pressure, regular cleans- following diseases that involve the skin are believed to be ing and drying of the skin, frequent change in position, caused, at least in part, by autoimmune reactions. Pre- Pemphigus (PEM-fi-gus) is characterized by the for- vention of pressure ulcer by these methods is far easier mation of blisters, or bullae (BUL-e) in the skin and mu- than treatment of an established ulcer. Both of these terms refer to lying down, al- leaves deeper areas of the skin unprotected from infection though pressure ulcers may appear in anyone with lim- and fluid loss, much as in cases of burns. Much like the frame of a build- produce movement ing, the skeleton must be strong enough to support and ◗ To serve as a storehouse for calcium salts, which may protect all the body structures. The in- Bones have a number of functions, several of which are dividual bones in these two divisions will be described in not evident in looking at the skeleton: detail later in this chapter. They may be flat (ribs, cra- ◗ To protect such delicate structures as the brain and the nium), short (carpals of wrist, tarsals of ankle), or irregu- spinal cord lar (vertebrae, facial bones). Humerus Cartilage Sternum Epiphyseal line Costal Ribs (growth line) cartilage Proximal Radius epiphysis Spongy (cancellous) Vertebral column bone (containing Carpals red marrow) Ilium (of pelvis) Ulna Endosteum Pelvis Compact bone Meta- Sacrum carpals Medullary (marrow) cavity Phalanges Artery and vein Femur Diaphysis Yellow marrow Patella Periosteum Calcaneus Fibula Tibia Tarsals Distal epiphysis Metatarsals Phalanges Figure 7-1 The skeleton. Even though the across the bone, from one side of the shaft to the other, spaces between the cells of bone tissue are permeated are many perforating (Volkmann) canals, which also with stony deposits of calcium salts, the bone cells them- house blood vessels and nerves. Bones are organs, with their The second type of bone tissue, called spongy, or can- own system of blood vessels, lymphatic vessels, and cellous, bone, has more spaces than compact bone. The cells in this type of bone are located in rings of bone tissue around a central haversian (ha-VER-shan) Checkpoint 7-1 A long bone has a long, narrow shaft and two canal containing nerves and blood vessels. Each ringlike unit with its cen- Checkpoint 7-2 What are the two types of osseous (bone) tis- tral canal makes up a haversian system, also known as an sue and where is each type found?

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The gene for type 1A has not yet been isolated buy cheap top avana 80 mg online, but it does follow an autosomal recessive pattern of inheri- Terri A order 80mg top avana with mastercard. It is KEY TERMS the diastrophic dysplasia sulfate transporter gene (DTDST) purchase top avana 80mg fast delivery, which is located on the long arm of chromo- Chondrocyte—A specialized type of cell that some 5 (5q32-q33 specifically) discount 80 mg top avana with visa. Abnormalities in the secretes the material which surrounds the cells in DTDST gene result in abnormal sulfation of proteins order 80mg top avana visa, cartilage. Fetal hydrops—A condition in which there is too The severity of mutation determines which disorder much fluid in the fetal tissues and/or cavities. The most severe of these disorders Micromelia—The state of having extremely short is type 1B. Similar to achondrogenesis type 1B, achondrogene- Polyhadramnios—A condition in which there is sis type 2 represents the most severe disorder of a group too much fluid around the fetus in the amniotic of disorders resulting from the mutation of a single sac. In addition to its important role in development and growth, collagen type 2 plays an important struc- sac, and/or fetal hydrops, a condition in which there is tural role in cartilage and in the ability of cartilage to too much fluid in the fetal tissues and/or cavities. Type 2, however, does not fol- with achondrogenesis are also often born in the breech low an autosomal recessive pattern of inheritance. Differences in traits shared by all subtypes Also, most of these mutations are considered autosomal of achondrogenesis dominant. However, some family members of affected Although all the subtypes of achondrogenesis share children may have the mutant gene without having the some characteristics, there are differences in some of disease. This is not a classical pattern of dominance and these characteristics between subtypes. Type 1 achondro- implies the involvement of other genes in the disease genesis is generally considered to be more severe than process. This is supported by the shorter limbs found in type 1 and the lower average birth weight of type 1 Demographics infants compared to type 2 infants. Additionally, both exact incidence is unknown, one estimate places the inci- groups have a number of subtle skeletal abnormalities in dence at 1 case in every 40,000 births. Traits found in type 1 not shared by Signs and symptoms type 2 achondrogenesis Traits found in all subtypes of achondrogenesis Type 1 achondrogenesis has two non-subtle charac- teristics that type 2 does not. These defects are formally known limbs (micromelia) and other skeletal abnormalities. The as either atrial septal defects, ventral septal defects, or a most defining feature of this condition is the extreme patent ductus arteriosus. Normally, Additionally, fetuses with achondrogenesis may oxygenated and deoxygenated blood are separated to have the condition polyhydramnios, a condition in which ensure enough oxygen makes it to important tissues, like there is too much fluid around the fetus in the amniotic the brain. Mixing the blood results in less oxygen being GALE ENCYCLOPEDIA OF GENETIC DISORDERS 15 cartilage tissues may be used to identify the type of disorder. Treatment and management As of 2001, there is no treatment for the underlying disorder. Parents should consider mental health and genetic counseling to deal with the grief of losing a child, and to understand the risks of the disorder recur- ring in subsequent children. It is important for genetic counseling purposes to determine the type of achondro- genesis that affected the child, since different types of achondrogenesis carry very different prognoses for future children. Type 1 is considered more severe, partly because infants with type 1 are more likely to be stillborn and generally succumb to the disorder earlier than infants with type 2 achondroge- nesis. Dartmouth-Hitchcock Medical Center— Diagnosis Division of Maternal-Fetal Medicine. Zuck, PhD 16 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Genetic profile IAchondroplasia Achondroplasia is caused by a mutation, or change, Definition in the fibroblast growth factor receptor 3 gene (FGFR3) located on the short arm of chromosome 4. Achondroplasia is a common form of dwarfism or short stature due to an autosomal dominant mutation (a Genes contain the instructions that tell a body how to mutation on one of the first 22 “non-sex” chromosomes) form. They are composed of four different chemical that causes an individual to have short stature with dis- bases–adenine (A), thymine (T), cytosine (C), and gua- proportionately short arms and legs, a large head, and nine (G). These bases are arranged like words in a sen- distinctive facial features, including a prominent fore- tence and the specific order of these four bases provide head and a flattened midface. FGFR (fibroblast growth factor receptor) genes pro- vide the instruction for the formation of a cell receptor. Description Every cell in the body has an outer layer called a cell Achondroplasia is a genetic form of dwarfism due to membrane that serves as a filter. There are ported into and out of the cells by receptors located on many causes for dwarfism, including hormone imbal- the surface of the cell membrane. The fibroblast growth fac- to a class of dwarfism referred to as a chrondrodystrophy tor receptor transports fibroblast growth factors into a or skeletal dysplasia.

Termination of drug effect by redistribution Sodium thiopental Ketamine Etomidate Sodium methohexital Propofol Midazolam B discount 80 mg top avana with visa. Intravenous anesthetics Lüllmann discount top avana 80mg on line, Color Atlas of Pharmacology © 2000 Thieme All rights reserved buy top avana 80 mg otc. During sleep purchase top avana 80mg mastercard, the brain generates a pat- Depending on their blood levels purchase top avana 80 mg amex, terned rhythmic activity that can be both benzodiazepines and barbiturates monitored by means of the electroen- produce calming and sedative effects, cephalogram (EEG). The Unlike barbiturates, benzodiaze- REM stage is characterized by EEG activ- pine derivatives administered orally ity similar to that seen in the waking lack a general anesthetic action; cere- state, rapid eye movements, vivid bral activity is not globally inhibited dreams, and occasional twitches of indi- (respiratory paralysis is virtually impos- vidual muscle groups against a back- sible) and autonomic functions, such as ground of generalized atonia of skeletal blood pressure, heart rate, or body tem- musculature. Thus, benzo- entered only after a preceding non-REM diazepines possess a therapeutic margin cycle. Frequent interruption of sleep considerably wider than that of barbitu- will, therefore, decrease the REM por- rates. With un- chemical structure, possess agonist ac- disturbed night rest, REM deficits are tivity at the benzodiazepine receptor (p. Due to their narrower margin of Hypnotics fall into different catego- safety (risk of misuse for suicide) and ries, including the benzodiazepines their potential to produce physical de- (e. Depen- hexobarbital, pentobarbital), chloral hy- dence on them has all the characteris- drate, and H1-antihistamines with seda- tics of an addiction (p. The erance, choral hydrate is suitable only site and mechanism of action of barbitu- for short-term use. Withdrawal of the hypnotic drug results in REM rebound, which ta- pers off only over many days (B). Since REM stages are associated with vivid dreaming, sleep with excessively long REM episodes is experienced as unre- freshing. Thus, the attempt to discon- tinue use of hypnotics may result in the impression that refreshing sleep calls Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Hypnotics 223 Waking state Sleep REM stage I Sleep stage II Sleep stage III Sleep stage IV REM-sleep= Rapid Eye Movement sleep NREM = No Rapid Eye Movement sleep A. Succession of different sleep phases during night rest Ratio REM NREM 5 10 15 20 25 30 Nights Nights Nights after without with withdrawal hypnotic hypnotic of hypnotic B. Effect of hypnotics on proportion of REM/NREM Barbiturates: Effect Paralyzing Pentobarbital Anesthetizing Pentobarbital Benzo- Hypnogenic diazepines: Hypnagogic Calming, anxiolytic Triazolam Triazolam Concentration in blood C. Concentration dependence of barbiturate and benzodiazepine effects Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. There is evidence that er, become unmasked at daytime when histaminergic, cholinergic, glutamater- other sedating substances (e. Via their ascending a synergistic interaction (impaired abil- thalamopetal projections, these neu- ity to concentrate or react). During and inhibitory activity decreases with sleep, input from the brain stem de- age, there is an increasing tendency to- creases, giving rise to diminished tha- wards shortened daytime sleep periods lamocortical activity and disinhibition and more frequent interruption of noc- of the GABA neurons (A). The risk of a re- propensity, causing it to remain low in bound decrease in sleep propensity af- the morning, to increase towards early ter drug withdrawal may be avoided by afternoon (midday siesta), then to de- tapering off the dose over 2 to 3 wk. Since benzodiazepine intoxication may Pharmacotherapeutic measures are in- become life-threatening only when dicated only when causal therapy has other central nervous depressants (etha- failed. Causes of insomnia include emo- nol) are taken simultaneously and can, tional problems (grief, anxiety, “stress”), moreover, be treated with specific ben- physical complaints (cough, pain), or zodiazepine antagonists, the benzo- the ingestion of stimulant substances diazepines should be given preference (caffeine-containing beverages, sympa- as sleep remedies over the all but obso- thomimetics, theophylline, or certain lete barbiturates. As illustrated for emo- tional stress (B2), these factors cause an imbalance in favor of excitatory influ- ences. As a result, the interval between going to bed and falling asleep becomes longer, total sleep duration decreases, and sleep may be interrupted by several waking periods. These drugs short- en the latency of falling asleep, lengthen total sleep duration, and reduce the fre- quency of nocturnal awakenings. Even with the longer-acting benzodiaz- epines, the patient awakes after about Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Hypnotics 225 Neurons with transmitters: Histamine Acetylcholine Glutamate Norepinephrine GABA Waking state NREM-sleep A. Changes of the arousal reaction in the elderly Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Furthermore, benzodiaze- cause rebound anxiety or insomnia and pines exert sedating, anticonvulsant, daytime confusion. All these actions result violent hostility, hallucinations), and from augmenting the activity of inhibi- their increased frequency in the elderly, tory neurons and are mediated by spe- has led to curtailed or suspended use of cific benzodiazepine receptors that triazolam in some countries (UK). The tolerated, the possibility of personality inhibitory transmitter GABA acts to changes (nonchalance, paradoxical ex- open the membrane chloride channels.

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