By I. Rocko. Greenwich University.

TREATM ENT PLAN: Based upon the criteria for initiating drug therapy of hypercholesterolem ia purchase 20 mg tadacip with amex, the physician generic tadacip 20 mg visa. Taylor 279 Introduction to Central Ner vous 2424 System Pharmacology Charles R purchase 20 mg tadacip. Craig REVIEW OF BASIC NEUROSCIENCE ther an EPSP (excitatory neurotransm itter) or an IPSP The functional unit of the central nervous system (CNS) (inhibitory transm itter) directly influence the num ber of is the neuron buy tadacip 20mg lowest price, and m ost neuropharm acological agents action potentials generated by the neurons with which have the neuron as their prim ary site of action 20 mg tadacip sale. Electron m icroscopic studies specialized receptors, for exam ple, those involved with have verified the sim ilarities and have shown the pres- proprioception, tem perature sensing, and so on. Neurons m ay synthesize, store, and release tial results in the calcium-facilitated release of a specific one or m ore transm itters. M any m ore synapses exist in chemical substance at the synapse between two neurons the CNS than in the periphery, and m any m ore neuro- (see Chapter 2). This am ount of transm itter at the synapse and thereby pro- potential difference change is known as a postsynaptic duce an exaggerated effect. This can be accom plished potential, and the direction of the potential change may by (1) increasing the rate of transm itter synthesis, (2) in- be either depolarizing or hyperpolarizing. A depolarizing creasing the rate of transm itter release, or (3) prolong- postsynaptic potential is called an excitatory postsynaptic ing the tim e the transm itter is in the synapse. If the magnitude of depolarization pro- m echanism can be accom plished either by inhibiting en- duced by EPSPs in the second neuron is great enough, an zym atic breakdown or by inhibiting the reuptake of a action potential produced in the second neuron will be previously released transm itter. If, on the other hand, a hyperpolarizing sponse by (1) decreasing synthesis of transm itter, (2) in- potential (known as an inhibitory postsynaptic potential, creasing transm itter m etabolism, (3) prom oting an in- or IPSP) is produced, it will inhibit the formation of de- creased neuronal uptake, or (4) blocking access of the polarizing action potentials. The first three processes tend M ost cells norm ally receive a large excitatory input to dim inish the am ount of transm itter in the synaptic with a m ore or less constant generation of action po- cleft. The net result of generated IPSPs will be to de- sess m ost of these capabilities at norepinephrine, crease the num ber of nerve im pulses per unit of tim e. Several im portant drugs interfere with 281 282 IV DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM Acetylcholine The discovery that A Ch was a transm itter in the periph- 1 eral nervous system form ed the basis for the theory of neurotransm ission. A Ch is also a neurotransm itter in the m am m alian brain; however, only a few cholinergic tracts have been clearly delineated. T Dopam ine 3 T Q uantitatively, dopam ine is the m ost im portant of the biogenic am ine neurotransm itters in the CNS. The three 4 m ajor distinct dopam inergic system s in the m am m alian brain are categorized according to the lengths of the T 7 T neurons. There is a system com prising ultrashort neu- 8 T T T TM rons within am acrine cells of the retina and peri- glom erular cells in the olfactory bulb. O f the several 5 interm ediate-length dopam inergic neuronal system s, the 6 best studied are neurons in the tuberobasal ventral hy- pothalam us that innervate the m edian em inence and the FIG U R E 24. The im portant in the regulation of various hypothalam ohy- steps are depicted for a typical neurotransmitter (T). Some pophysial functions, including prolactin release from the neurotransmitters do not follow this scheme. The best-categorized of the dopam ine action potential; site 2, synthesis of T from T ; site 3, neuronal system s are the long projections from nuclei in storage of T in vesicles; site 4, release of T in response to the substantia nigra and ventral tegm ental areas to the the action potential; site 5, binding of T to receptor; site 6, lim bic cortex; other lim bic structures, including the intracellular response to action of T at site 5; site 7, am ygdaloid com plex and piriform cortex; and the neo- reuptake of T across neuronal membrane; site 8, striatum (prim arily the caudate and putam en). In general, dopam ine appears to be an in- function continually to slow the num ber of action po- hibitory neurotransm itter. The effects of stim ulating an excita- have been identified; the m ost im portant and best stud- tory pathway can appear to be exaggerated if norm al in- ied are the D 1-and D 2-receptor groups. The D 2-receptor de- creases cA M P, blocks certain calcium channels, and opens certain potassium channels. CENTRAL NERVOUS SYSTEM NEUROTRANSM ITTERS Norepinephrine A large num ber of CNS neurotransm itters have been M ost central noradrenergic neurons are located in the either tentatively or positively identified. W hile a de- nucleus locus ceruleus of the pons and in neurons of tailed discussion of the various central neurotransm it- the reticular form ation. Fibers from these nuclei inner- ters and the criteria for their identification is beyond the vate a large num ber of cortical, subcortical, and spino- scope of this text, a sum m ary of the m ost im portant m edullary fields. The m am - tonin are present in all of the cells containing this am ine m alian CNS contains both - and -adrenoceptors. Serotonin is initially oxidatively deam i- nated to form 5-hydroxyindoleacetaldehyde; this com - Epinephrine pound is subsequently rapidly oxidized to the m ajor m etabolite 5-hydroxyindoleacetic acid, which is excreted Epinephrine is found only in very low concentrations in in the urine. M uch of the serotonin released in the brain the m am m alian CNS, and it is unlikely to play a m ajor at synapses is taken back into the initial neuron by an ac- role as a neurotransm itter. Serotonin Actions and Site of Actions Serotonin (5-hydroxytryptamine, or 5HT) is present in M ost of the serotonin in the brain is in the brainstem, the brain as well as in the periphery.

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These bind diverse substances buy generic tadacip 20mg on line, in- clude cellular proteins cheap tadacip 20 mg, for this would cluding toxins purchase tadacip 20 mg mastercard, permitting them to be mean cell death tadacip 20 mg otc. They improve the consistency of bowel Oral rehydration solution (g/L of contents; beyond that they are devoid boiled water: NaCl 3 purchase tadacip 20 mg free shipping. Oral administra- tion of glucose-containing salt solutions enables fluids to be absorbed because toxins do not impair the cotransport of Na+ and glucose (as well as of H2O) through the mucosal epithelium. In this manner, although frequent discharge of stool is not prevented, dehydration is successfully corrected. Activation of opioid recep- tors in the enteric nerve plexus results in inhibition of propulsive motor activ- ity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opi- um tincture (paregoric) containing mor- phine. Because of the CNS effects (seda- tion, respiratory depression, physical dependence), derivatives with periph- eral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Antidiarrheals and their sites of action Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Following its secretion from liver into Choleretics are supposed to stimu- bile, water-insoluble cholesterol is held late production and secretion of dilute in solution in the form of micellar com- bile fluid. This principle has little thera- plexes with bile acids and phospholip- peutic significance. When more cholesterol is secreted Cholekinetics stimulate the gall- than can be emulsified, it precipitates bladder to contract and empty, e. Cholekinetics are em- lesterol concentration in bile is below ployed to test gallbladder function for saturation. This Pancreatic enzymes (B) from effect can be achieved by long-term oral slaughtered animals are used to relieve administration of chenodeoxycholic excretory insufficiency of the pancreas acid (CDCA) or ursodeoxycholic acid (! Normally, secretion of ring, stereoisomeric bile acids (position pancreatic enzymes is activated by of the 7-hydroxy group being! Normally, they repre- terohormone that is released into blood sent a small proportion of the total from the duodenal mucosa upon con- amount of bile acid present in the body tact with chyme. With oral administra- (circle diagram in A); however, this in- tion of pancreatic enzymes, allowance creases considerably with chronic ad- must be made for their partial inactiva- ministration because of enterohepatic tion by gastric acid (the lipases, particu- cycling, p. Small losses via the feces are made up Antiflatulents (carminatives) serve by de novo synthesis in the liver, keep- to alleviate meteorism (excessive accu- ing the total amount of bile acids con- mulation of gas in the gastrointestinal stant (3–5g). Aborad propulsion of intestinal moves the need for de novo synthesis of contents is impeded when the latter are bile acids. Defoaming plied gains an increasingly larger share agents, such as dimethicone (dimethyl- of the total store. UCDA is more effective (daily dose, 8–10 mg) and better toler- ated than is CDCA (15 mg/d; frequent diarrhea, elevation of liver enzymes in plasma). Other Gastrointestinal Drugs 181 CA : Cholic acid DCA : Desoxy-CA UDCA UDCA : Ursodesoxy-CA CDCA : Chenodesoxy-CA Synthesis of bile acids to maintain store Gall-stone formed by cholesterol DAA DCA CDCA CA CDCA CA UDCA UDCA Ileum Excretion in feces A. Gallstone dissolution “Pancreatin” of slaughter animals: Protease, Amylase, Lipase Stomach Duodenum CK/PZ Addition Fat- of containing Circulation dimethicone chymus Pancreatic enzyme “Defoaming” B. Carminative effect of their replacement dimethicone Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Benzodiazepines en- hance the effectiveness of the inhibitory The smallest structural unit of skeletal transmitter GABA (p. In executing motor pro- as clonidine and tizanidine probably act grams, the brain sends impulses to the presynaptically to inhibit release of ex- spinal cord. Efferent axons course, bun- in (cause of wound tetanus) and strych- dled in motor nerves, to skeletal mus- nine diminish the efficacy of interneu- cles. Simple reflex contractions to sen- ronal synaptic inhibition mediated by sory stimuli, conveyed via the dorsal the amino acid glycine (A). As a conse- roots to the motoneurons, occur with- quence of an unrestrained spread of out participation of the brain. Neural nerve impulses in the spinal cord, motor circuits that propagate afferent impuls- convulsions develop. The involvement es into the spinal cord contain inhibit- of respiratory muscle groups endangers ory interneurons. The toxin blocks exo- Neuromuscular transmission (B) of cytosis of ACh in motor (and also para- motor nerve impulses to the striated sympathetic) nerve endings.

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Drugs with predomi- action and the oral bioavailability render the drug use- nantly antitussive effects are described later in this ful for the treatment of opioid addiction by decreasing chapter cheap 20 mg tadacip mastercard. Certain of the opioids buy tadacip 20mg with mastercard, such as propoxyphene the rapid highs and lows associated with fast-onset buy generic tadacip 20mg online, and meperidine buy 20 mg tadacip mastercard, are relatively devoid of antitussive short-duration drugs such as heroin discount 20mg tadacip with amex. Tolerance and Physical Dependence A derivative of methadone, L- -acetyl-methadol All of the opioid agonists produce some degree of tol- (LAAM) has been approved for the treatment of opi- erance and physical dependence. In some addicts whose degree of toler- mechanisms underlying tolerance and physical depend- ance is not known, the patient is first given methadone ence are unclear. It is known, however, that intracellular to stabilize the withdrawal signs and is then switched to mechanisms of tolerance to opioids include increases in LAAM. LAAM has an advantage over methadone in calcium levels in the cells, increased production of that it has a longer duration of action. Dosing is re- cAMP, decreased potassium efflux, alterations in the quired only three times per week in most addicts to pre- phosphorylation of intracellular and intranuclear pro- vent withdrawal. However, tolerance to the respiratory opium preparation paregoric to reduce withdrawal depressant and emetic effects of the opioids occurs signs. The miotic and constipative effects of the Other treatments for opioid addiction are described opioids rarely show tolerance. Tolerance to one opioid usually renders a patient cross-tolerant to other opioids but not to drugs of other Morphine classes. The predominant effects of change in receptor number induced by the chronic opi- morphine are at the -opioid receptor, although it in- oid administration. Morphine is trinsic activity would need to occupy fewer receptors to indicated for the treatment of moderate to severe and exert an effect and would be less affected by changes in chronic pain. It is useful preoperatively for sedation, 26 Opioid and Nonopioid Analgesics 321 anxiolytic effects, and to reduce the dose of anesthetics. Opioids with less antitussive effects, commonly used drug for the treatment of dyspnea- such as meperidine, are better for such situations. It is thought that mor- When used via the epidural route, the site for injec- phine reduces the anxiety associated with shortness of tion must be free of infection. In addition, the use of breath in these patients along with the cardiac preload corticosteroids by the patient should be halted for at and afterload. In particular, the long- of the risk of a rise in intracranial pressure from vasodi- acting preparations of morphine, such as MS-Contin lation and increased cerebrospinal fluid volume. In ad- and Ora-Morph, are described as the cornerstone of dition, in such patients the onset of miosis following opi- pain treatment in cancer patients, either alone or in oid administration can mask the pupillary responses combination with nonopioids. Morphine is the most commonly used analgesic drug The clearance of morphine and its active metabolite, administered via the epidural route because it is potent, morphine-6-glucuronide depends on adequate renal efficacious, and hydrophilic. The elderly are particularly susceptible to ac- drug, the slower the onset and the longer the duration cumulation of the drugs, hence respiratory depression of action following epidural administration. Morphine, like all opioids, passes through or continuous infusion of morphine is used to provide the placenta rapidly and has been associated with pro- pain relief in thoracic and abdominal surgical patients longation of labor in pregnant women and respiratory and in cancer patients at high risk for developing side depression in the newborn. Since morphine Morphine and other opioids exhibit intense sedative does not produce anesthesia via the epidural route, the effects and increased respiratory depression when com- patient is able to move about normally; motor function bined with other sedatives, such as alcohol or barbitu- is preserved. Increased sedation and toxicity are observed is that certain types of pain are relatively unresponsive, when morphine is administered in combination with such as that associated with visceral stimuli, as in pan- the psychotropic drugs, such as chlorpromazine and creatitis, and neuropathic pain from nerve deafferenta- monoamine oxidase inhibitors, or the anxiolytics, such tion. While the IV ad- vere than those observed following the systemic admin- ministration of naloxone reverses the toxic effects of istration of the drug, and can be alleviated by elevation morphine, naloxone has a short duration of action and of the head of the patient at a 30-degree angle. Patients must be administered repeatedly at 30- to 45minute in- may also itch because of histamine release. The use of an in- Codeine and Other Phenanthrene dwelling catheter allows the patient to administer the Derivatives drug at frequent intervals for pain relief. PCA systems allow patients the freedom to assess the need for their Like morphine, codeine is a naturally occurring opioid own analgesia and to titrate a dose tailored to their found in the poppy plant. Dependence is rarely observed in patients using treatment of mild to moderate pain and for its antitus- PCA for acute pain management. It is widely used as an opioid antitussive be- cause at antitussive doses it has few side effects and has excellent oral bioavailability. Codeine is metabolized in Adverse Effects and Contraindications part to morphine, which is believed to account for its The opioids generally have a high level of safety when analgesic effect. However, there are several opioids in combination with nonopioids for the relief of notable exceptions. The administration of 30 mg of codeine in combi- contraindicated in patients with hypersensitivity reac- nation with aspirin is equivalent in analgesic effect to tions to the opioids. The combina- used in patients with acute bronchial asthma and should tion of the drugs has the advantage of reducing the 322 IV DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM amount of opioid required for pain relief and abolition Like morphine, meperidine has an active metabo- of the pain via two distinct mechanisms, inhibition of lite, normeperidine, formed by N-demethylation of prostanoid synthesis and opioid inhibition of nocicep- meperidine.

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