Amantadine

By D. Jerek. Wartburg College. 2019.

Examples include the use of eutectic mixtures and supersaturated systems to enhance the transdermal penetration of drugs (see Chapter 8) amantadine 100 mg mastercard. Other formulation strategies include altering the formulation pH and tonicity to effect favorable absorption cheap amantadine 100 mg. Various further strategies are specific for the route in question, for example the use of iontophoresis to enhance the transdermal delivery of drugs. The following chapters provide a more in-depth discussion of each of the major routes of drug delivery and discuss both advantages and disadvantages of these routes. The existing technologies employed to maximize delivery using the various routes is discussed along with the perceived challenges and opportunities for the future. Explain the following terms: (a) sustained release, (b) zero-order release, (c) bio-responsive release, (d) rate-controlled release and (e) targeted drug delivery. Outline the advantages and disadvantages of the following routes of administration: (a) parenteral, (b) oral and (c) pulmonary. Outline how the physicochemical properties of a dosage form can be modulated to improve drug absorption. Such systems are most commonly used for 74 sustained parenteral administration, including ocular and subcutaneous drug delivery. This chapter focuses on such implant systems and the mechanisms of rate control which form an intrinsic component of implantable systems. As these rate control mechanisms are applicable to many other drug delivery systems, this chapter also serves as a general introduction to the methods of rate control which are achievable using advanced drug delivery and targeting strategies. Implants are available in many forms, including: • polymers, which can be biodegradable or non-degradable and are available in various shapes (rod, cylinder, ring, film, etc. They are commonly implanted subcutaneously, either into the loose interstitial tissues of the outer surface of the upper arm, the anterior surface of the thigh or the lower portion of the abdomen. However, implants may also be surgically placed in, for example, the vitreous cavity of the eye (intravitreal implant), or intraperitoneally. Scientists further fabricated pellet-type implants comprising other steroidal hormones including testosterone, progesterone, deoxycorticosterone and dromostanolone propionate. Release from such pellet-type implants is governed by the dissolution of the particular drug moiety in the body fluids and thus is not amenable to external control. A pellet-type implant also lacks pellet-to-pellet reproducibility in the rate of drug release. In the early 1960s, it was reported that hydrophobic small molecular weight compounds permeated through a silicone rubber capsule at relatively low rates. When implanted in animals, the system released drugs at reasonably constant rates and also elicited little inflammation at the site of implantation. The use of a silicone elastomer as a diffusion barrier to control the release of compounds such as steroidal hormones, insecticides, anesthetics and antibiotics was later demonstrated. The rate of drug release was subject to external control by manipulating the thickness, surface area, geometry and chemical composition of the silicone elastomers. As a silicone rubber membrane is not permeable to hydrophilic or high molecular weight compounds, concerted efforts were made to develop other biocompatible polymers for use in implantable devices. Such polymers include poly(ethylene-co-vinyl acetate), poly (ethylene), poly(propylene), poly(hydroxymethyl methacrylate), poly(lactide-co-glycolide), poly (anhydrides) and poly(ortho esters). The characteristics and applications of each important polymer family will be discussed later in this chapter. A brief overview of both the advantages and disadvantages of implantable drug delivery is given below. However, under these regimens, patients are often required to stay in hospital during administration for continuous medical monitoring. A short-acting drug exacerbates the situation, as the number of injections or the infusion rate must be increased, in order to maintain a therapeutically effective level of the drug. In contrast, implantation therapy permits patients to receive medication outside the hospital setting, with minimal medical surveillance. Implantation therapy is also characterized by a lower incidence of infection-related complications in comparison to an indwelling catheter-based infusion system. A person can forget to take a tablet, but drug delivery from an implant is largely independent of patient input. Some implantable systems involve periodical refilling, but despite this factor the patient has less involvement in delivering the required medication. This bypassing effect is particularly of benefit to drugs which are either absorbed poorly or easily inactivated in the gastrointestinal tract and/or the liver before systemic distribution. From a regulatory perspective, it is regarded as a new drug product and can extend the market protection of the drug for an additional 5 years (for a new drug entity) or 3 years (for existing drugs). This requires the appropriate surgical personnel, and may be traumatic, time-consuming, cause some scar formation at the site of implantation and, in a very small portion of patients, may result in surgery- related complications. Although a biodegradable polymeric implant does not require surgical retrieval, its continuing biodegradation makes it difficult to terminate drug delivery, or to maintain the correct dose at the end of its lifetime. Therefore, most systems have a limited loading capacity, so that often only quite potent drugs, such as hormones, may be suitable for delivery by implantable devices. If a new biomaterial is proposed to fabricate an implant, its safety and biocompatibility must be thoroughly evaluated to secure the approval of regulatory authorities.

The common pneumatic system is open to criticism because of the nonproportionality introduced by the compressibility of air discount amantadine 100 mg online, the general inconvenience of keeping the system free from leaks purchase amantadine 100mg with visa, and the awkward readjustment when S throws the recorder off scale by a movement. The Indiana study considered two aspects of respiration: amplitude and breathing cycle time (the inverse of rate). In amplitude the response in truth telling was an increase, with the maximum 5 to 10 sec after he delivery of a question. The fact that a smaller increase in amplitude typically indicates deception requires an operator to make a sort of inverted interpretation on this point. There seems to be much better discrimination between the two conditions when these measures are used in a long series of questions; i. It may be that breathing in the early part of a series is made irregular by a reaction to the general situation. After some adaptation it becomes possible to compare the responses to questions in purer form. According to some later work (8) the inhibition of breathing seems rather characteristic of anticipation of a stimulus. One drawback in the use of respiration as an indicator is its susceptibility to voluntary control. If an S wished to produce a confused record he could probably do so by alternating over and under breathing, if he could keep up this or another program in the face of questions. If an examinee knows that changes in breathing will disturb all -145- physiologic variables under control of the autonomic division of the nervous system, and possibly even some others, a certain amount of cooperation or a certain degree of ignorance is required for lie detection by physiologic methods to work. Respiration, therefore, on balance in the present state of knowledge seems to be one of the better measures. Inbau (20) and others write that blood pressure is the main channel for the deception reaction in a real situation, although galvanic skin response may have greater power in the laboratory. The evidence is that the rise will generally be greater when S is lying than when telling the truth. In using this measure, the operator, consciously or unconsciously, uses some sort of cut-off to separate the two categories. The content of neutral questions will produce variations in the response, and one must then decide whether a response to a critical question is "positive" if it is larger than any other, or if it is larger than average by some amount. The instrument currently in use consists of a pressure cuff similar to that used in medical practice, but equipped with a side branch tube which connects to a tambour through a pressure reducer. The method is to inflate the cuff (on the upper arm) to a point between systolic and diastolic pressure; that is, to about 100 mm of mercury. Under these circumstances there is a flow of blood to the lower arm only during the upper half of the pulse wave, and there is practically no venous return from the arm since the cuff pressure far exceeds the pressure in the veins, and occludes them. The side branch from the cuff will convey pressure variations to the -146- tambour and its stylus. Variations produced both by the pulse and by those slower changes are referred to as systolic blood pressure variations. This criticism has made little impression on those who use the method, since they can exclaim, with some justification, "But it works! The practical stoppage of circulation can become, in the course of a sitting, quite painful, and in a long sitting, dangerous. Operators, who are aware of these consequences, release the pressure from time to time to restore circulation. The side effects are such as to produce reactions in the other autonomically controlled variables which one may be measuring, and even in the blood pressure itself. The Indiana study used a different method, unfortunately also open to these objections to occluding the blood supply. By mechanical means, a steadily increasing pressure was applied to a cuff and the point of complete occlusion determined by means of a pulse detector on the lower arm. The experimental results confirm the opinion that it is one of the better indicators of deception. Again discrimination is poor (almost nil) in the early part of a sitting and improves to a high point later. Recently the writer (7) investigated the requirements of continuous arterial oressure measurement, and proposed a "closed circuit" method which uses a strain gauge applied to an artery with very little pressure. This device is simple to construct and use and seems well suited to the recording of variations in arterial pressure, although it will not as now developed indicate the base level of pressure. It has been used in a number of tests and experiments to record reaction to stimuli of various sorts (questions, flashes of light, and warning and reaction signals in decision situations). Although it has not been tested in a detection situation, there is good reason to think that it will do at least as well as the occlusion or near occlusion methods. With a certain type of situation he was able to detect lying better than 90 per cent of the time. Recovery, however, is typically slow in this variable, and in a routine examination the next question is likely to be introduced before recovery is complete. On the other hand, long term changes in skin resistance may have a certain significance.

By means of a posthypnotic suggestion the hypnotist induced his victim to confess to crimes that the hypnotist had committed purchase amantadine 100 mg without a prescription. Throughout the entire affair order 100mg amantadine mastercard, which lasted for five years, the schoolteacher had no recollection of the hypnotic sessions. The schoolteacher was convicted, but began to suspect the nature of his relationship with his neighbor on the basis of a chance remark. After many appeals he was recommended for examination to Kroener, who eventually uncovered the true state of affairs by re-hypnotizing the schoolteacher and thereby causing him to remember all the hypnotic experiences with his neighbor. The study by Mayer (44), usually called the Heidelberg case, involves a twenty-four-year-old housewife who was victimized by a man who posed as a doctor treating her. At first he swindled money from her under the pretense of curing her of various complaints which he himself had induced by hypnotic suggestion. Later, presumably by means of his hypnotic influence, he compelled her to have sexual relations with himself and with his friends. The hypnotist was arrested and convicted despite his consistent plea of not guilty. The third case, investigated by Reiter (58), deals with a man who was sentenced to prison for helping the Germans during the last war. While in prison he met a man who especially fascinated him because of his apparent knowledge of religion, mysticism, and occultism. They were alone in the same cell for nearly eighteen months, besides being together in the workshop every day. After awhile, the hypnotist informed his victim that he (the hypnotist) was an instrument employed by the guardian spirit, and that the guardian spirit was speaking to the victim through the medium of the hypnotist. From that time on the victim felt that -189- he had to carry out all the orders of the guardian spirit. After they were released from prison the men continued their relationship — and the guardian spirit continued to make demands. The guardian spirit ordered his victim to turn over his wages to the hypnotist; he found a girl for the victim to marry and ordered him to do so, which he did; he ordered him to procure money in order to establish a political organization through which they could create a better society and unite the Scandinavian countries, the goal being the salvation of mankind. It was toward the latter end that the guardian spirit, through the medium of the hypnotist, pointed out the bank that the victim was to rob. The robbery was accomplished, and a year later orders came for another bank robbery. During the execution of this task the victim committed murder and was apprehended. In some manner the subject was dissatisfied and the individual who later became the hypnotist provided gratification. In the first case, the schoolteacher lived alone, and appeared somewhat isolated because of insufficient social contacts. The neighbor provided friendship and initially performed many minor services for him. In the Heidelberg case the subject initially met the hypnotist in a situation where he presented himself as a physician who could relieve a symptom that was causing her acute distress. The subject appeared to have had psychosomatic symptoms before contact with the hypnotist, which might have reflected tension in her marriage. In the last case the subject was dejected with intense feelings of worthlessness, as an aftermath of collaboration during the war. The intensity of this relationship can be inferred from the fact that the subject at the time began to feel considerably more comfortable. Thus, in each case the relationship between subject and hypnotist was such that the former derived need gratification from the association. Frequently relationships exist between two individuals that have no connection with hypnosis but are marked by intense feelings and a strong tendency on the part of one individual to comply with whatever requests are made of him by the other. If this type of relationship exists between two individuals, it would seem unnecessary to employ hypnosis to explain behavior on the part of one person which benefits the other. Only in the absence of this kind of pre- -190- existing relationship is it meaningful to speak of hypnosis as being a necessary prerequisite for the behavior. However, if we are to make inferences from these data to the situation of hypnosis in interrogation it is necessary to keep in mind that the relationship between the interrogator and the subject is not often comparable to the long-term relationships which existed in the cases cited. The experimental laboratory studies suffer from the defects of a pseudo-reality situation where the "nansgressive acts" cannot be defined as such in the context of the total situation, and from the defect of the mutually shared wishes and motives of experimenter and subject. The only three cases of criminal acts apparently involving hypnosis which are reliably reported in the recent literature all involve an intense emotional relationship between hypnotist and subject. In the absence of meaningful evidence, any conclusions reached must be of a conjectural nature. Experimental tests of the question are feasible, but would require camouflage of the institutional responsibilities of the investigators. The author would postulate that only in rare interrogation subjects would a sufficiently deep trance be obtainable to even attempt to induce the subject to discuss material which he is unwilling to discuss in the waking state. The kind of information which can be obtained in those rare instances is still an unanswered question.

Men have undergone prolonged fasts without significant impairment of their highest faculties cheap amantadine 100mg without a prescription. And buy amantadine 100mg otc, so far as dangerous situations are concerned, there are some who are stimulated or even exhilarated by them, and many others who act as if they do not regard them as dangerous at all. Thus, hunger, pain, signals of danger, and similar forms of sensory input cannot be shown to be necessarily toxic to the human brain, for, under the right circumstances, any individual apparently can -34- tolerate them indefinitely. The weight of evidence is that it is not the sensory input itself, but the reaction of the individual to this input which may adversely affect his brain function. This is not so with isolation, sleep deprivation, and fatigue, where the effects are intrinsically adverse, and the reaction of the individual is a factor only in determining how long these effects can be withstood. With hunger, pain, and signals of danger, the adverse effects on brain function may be entirely the result of the reaction of the individual. Activities of the brain, initiated in response to incoming information, lead to an impairment of brain function. This special vulnerability of the brain to its own activities, long suggested by clinical observation, has recently received experimental support (24, 25). Hunger The syndrome commonly associated with the reaction to hunger is slow in developing, but it can be expected to occur in the majority of those who are exposed to prolonged hunger from any cause (18, 67). It has been seen among starved populations (1), among inmates of concentration camps (54, 70), and among prisoners of war (47, 61, 67, 104), and has been reproduced experimentally (18, 67, 82). This and other rigors of the prison camp experience were probably responsible for a good deal of the symptomatology that occurred among American prisoners in Korea (79, 105, 113). People deprived of food very soon develop a persistent hunger, which does not leave them until death approaches or nutrition is restored (18, 21, 54, 67). Accompanying this hunger there is a constant preoccupation with food, which may encompass the greater part of waking thoughts and activity (18, 54, 67). As starvation progresses, the niceties of dress and behavior are neglected, and if the lack of food carries with it a threat of death, behavior may cease to be governed by the restraints of "honesty," "unselfishness," "pride," and "honor," which are active under normal circumstances; in short, the very highest integrative functions drop away (18, 54, 67). During the earlier stages of hunger, irritability and emotional lability are the rule, but later profound and continuing apathy occurs (18, 19, 54, 61, 67, 104). In the most advanced stages of inanition, defects of memory, confusion, hallucinations, delusions, and intellectual deficits become evident (1, 54, 67). Advanced inanition is associated with major changes in the physical state of the individual. Although it is quite possible that this state is directly responsible for the derangement in brain function which takes place, the disturbances of behavior and of mood which occur during the -35- early part of starvation are present long before any significant derangement of the internal milieu can be demonstrated (18, 19, 67). In starved communities, in concentration camps, and in experimental situations, some people endure hunger for a long time, and maintain their highest level functions with very little evidence of disorganization until the effects of illness or lack of food supervene (1, 18, 19, 54, 67, 70). Such people, although they do feel hunger and are aware of it, are able to engage in thought and behavior other than that centering around a preoccupation with food; their symptoms are less outstanding and their behavior is more "normal. Pain The investigation of pain has been especially enlightening in this regard, because many careful laboratory studies have defined the difference between the "sensation of pain" and the "reaction to pain" (3, 50, 52, 110, 132, 133). The sensation of pain seems to be roughly equal in all men, that is to say, all people have approximately the same threshold at which they begin to feel pain, and when carefully graded stimuli are applied to them, their estimates of severity are approximately the same (6, 28, 48, 50, 51, 71, 85). In general, the reaction to pain is in proportion to its severity, and the most intense pains incapacitate men for any sort of complex function during the period of their duration. Yet exception must be taken even to this statement, for when men are very highly motivated, as they may be when their own lives or the lives of others are at stake, they have been known to carry out rather complex tasks while enduring the most intense pain. The variability of human reactions to the moderately severe grades of pain, such as those found in various diseases, is notorious. Some people perform quite effectively over many years while experiencing the pains of chronic headache, peptic ulcer, arthritis, or similar conditions; others with like amounts of pain are severely incapacitated (3, 6, 7, 8, 28, 48, 50, 63, 69, 78, 93, 94, 103, 112, 125, 132, 133). It is characterized by withdrawal from the more complex and responsible functions of life, a certain amount of irritability -36- and emotional lability, and concentration upon personal comfort and survival at the expense of the needs of others and of the society. Under experimental circumstances, those who try to "carry on" while experiencing moderate pain show impairment of their performance on complex tasks, impairment of decision making, loss of efficiency, and difficulty in estimating time (8) — symptoms which would be expected to occur in the early stages of the “brain syndrome” and much like those of people who have suffered the destruction of a small segment of their cerebral hemispheres (24, 25). It is possible that the differences in the way that various people react to pain may be partly determined by their constitutions, for it sometimes appears to the clinical observer that people of “mesomorphic” build, the heavily muscled and big-boned individuals, are those who react to pain with stoicism or with anger and a mobilization for action that temporarily enhances their performance; whereas the lighter and asthenic “ectomorph” often reacts to pain with withdrawal, incapacitation, self- concern, and anxiety. Yet the exceptions to this are many, and the variations in the reaction of the same person from time to time are great. In general, it appears that whatever may be the role of the constitutional endowment in determining the reaction to pain, it is a much less important determinant than is the attitude of the man who experiences the pain (3, 6, 7, 48, 50, 52, 69, 94, 110, 112, 125, 132, 133). Threat Threats of any sort, direct, implied, or symbolic, are not necessarily derived from sensory input which is intrinsically “unpleasant. Complex situations, symbols, and small cues arouse potent reactions entirely because of the interpretation put upon them. Some men react to ostensibly dangerous situations with continued effective performance. When men react to such situations as threatening, and when their reactions are characterized by anxiety or other intense emotions, these reactions may disorganize their brain function.

Pharmacokinetics When taken orally best amantadine 100 mg, podophyllotoxins are only moderately ab- sorbed purchase 100mg amantadine fast delivery. Metabolism and excretion Podophyllotoxins undergo liver metabolism and are excreted pri- marily in urine. Pharmacodynamics Although their mechanism of action isn’t completely understood, podophyllotoxins produce several biochemical changes in tumor cells. Arresting development At low concentrations, these drugs block cells at the late S or Adverse G2 phase. Other adverse reactions Pharmacotherapeutics include: Etoposide is used to treat testicular cancer lymphomas, prostate • nausea and vomiting cancer, and small-cell lung cancer. Monoclonal antibodies include: • alemtuzumab • gemtuzumab ozogamicin • ibritumomab tiuxetan • rituximab • trastuzumab. Pharmacokinetics Because of their large protein molecule structure, monoclonal an- tibodies aren’t absorbed orally. They may have a limited distribu- tion as well as a long half-life, sometimes measured in weeks. Pharmacodynamics Monoclonal antibodies bind to target receptors or cancer cells and cause tumor death via several mechanisms: They may induce pro- grammed cell death; they may recruit other elements of the im- mune system to attack the cancer cell; or they may deliver a dose of a toxic chemotherapy drug (gemtuzumab) or radiation (ibritu- momab) to the tumor site. Drug interactions Although no interactions have been noted with alemtuzumab, mul- tiple drug interactions are associated with other monoclonal anti- bodies. These agents are derived from tions that have occa- a naturally occurring alkaloid from the Chinese tree Camptotheca sionally been fatal. Currently available topoisomerase I inhibitors in- These include fever, clude: chills, shortness of • irinotecan • topotecan. In addition, the fol- Pharmacokinetics lowing adverse reac- Both irinotecan and topotecan are minimally absorbed and tions can occur: must be given I. Topotecan pression and an in- is metabolized by the liver, although renal excretion is a signifi- creased risk of oppor- cant path for elimination. Topoisomerase I inhibitors act against both solid tumors and hematologic malignancies: • Irinotecan is used to treat colorectal cancer and small-cell lung cancer. Drug interactions Topoisomerase I inhibitors, particularly irinotecan, can interact Adverse with other drugs. Common reactions • Prochlorperazine administered with irinotecan can increase the The more common ad- incidence of extrapyramidal toxicities. Drugs used for this new approach to cancer treat- ment include: and production of saliva • bortezomib • nausea, vomiting, and • gefitinib loss of appetite • imatinib. Pharmacokinetics Additional reactions Bortezomib isn’t absorbed orally and must be given I. It’s exten- Occasionally, these re- sively distributed into body tissues and metabolized by the liver. It’s 95% bound to plasma proteins and is exten- itchy sively metabolized by the liver. Proteolysis by bortezomib results in disruption of the normal homeostatic mech- anisms and leads to cell death. This inhibition blocks signaling pathways for growth, proteins that cause survival, and metastasis of cancer. Pharmacotherapeutics Bortezomib is used to treat multiple myeloma that has relapsed af- ter standard chemotherapy. Gefitinib is used as a single agent for patients with non–small- cell lung cancer that hasn’t responded to two standard chemother- apy regimens. Drug interactions Bortezomib, gefitinib, and imatinib have been associated with some drug interactions. Adverse reactions to targeted therapies Patients should avoid becoming pregnant while taking borte- farction, pulmonary edema, and pericardial effusion (less com- zomib, gefitinib, or imatinib because in animal studies these mon reactions) drugs crossed the placental barrier, causing fetal harm and Gefitinib death. These drugs include: • arsenic trioxide • asparaginases • procarbazine • hydroxyurea • interferon • aldesleukin • altretamine • paclitaxel (taxane) • docetaxel (taxane). Arsenic trioxide is a commercially available treatment for pa- tients with acute promyelocytic leukemia (a rare form of acute myeloid leukemia). The metabolism of arsenic trioxide involves reduc- cause electrocardio- tion via arsenate reductase, with subsequent methylation to inac- gram abnormalities, tive metabolites in urine. Arsenic is distributed in the heart, liver, which could progress to kidney, lung, hair, and nails. It’s also being in- • muscle and bone vestigated for treatment of multiple myeloma. Fever, After administration, asparaginase remains inside the blood ves- headache, abdominal sels, with minimal distribution elsewhere. The metabolism of as- pain, pancreatitis, coag- paraginase is unknown; only trace amounts appear in urine. Pharmacodynamics Rising risk Asparaginase and pegaspargase capitalize on the biochemical dif- Asparaginase and peg- ferences between normal cells and tumor cells.

Its effects on the cardiovascular system are very similar to those of phenoxybenzamine 100 mg amantadine visa, 4 buy 100mg amantadine with mastercard. The primary application for phentolamine is for the control of hypertensive emergencies, most notably caused by pheochromocytoma. It has also been used to treat hypertensive crises secondary to monoamine oxidase inhibitor-sympathomimetic amine interactions and for withdrawal of clonidine, propranolol, or other antihypertensives. In patients with congenital or acquired cardiac defects, phentolamine is used to induce peripheral vasodilation and afterload reduction after cardiopul- monary bypass surgery. Similar to phenoxybenzamine, the use of phentolamine during bypass is associated with reduced systemic anaerobic metabolism and more uniform body perfusion. Pre- sumably, improved mixing of blood would be caused by both a reduction in afterload and an alteration in the diastolic function of the right ventricle, allow- ing more left-to-right shunting across the atrial septal defect. Interestingly, although widely used in the pediatric patients, literature describing its use is scant. Mechanism of Action Phentolamine is a long-acting, α-receptor blocking agent that can produce and maintain a “chemical sympathectomy” by oral adminis- tration. It increases blood flow to the skin, mucosa, and abdominal viscera, and lowers both supine and erect blood pressures. Phentolamine works by blocking α-receptors present in vascular smooth muscle, thereby inducing vasodilation. It also blocks receptors for serotonin, and it causes release of histamine from mast cells. Phentolamine is a competitive antagonist, meaning that blockade can be surmounted by increasing the concentration of agonist drugs. Dosing Phentolamine should be slowly titrated to the desired effect after a small initial dose and with rigorous hemodynamic monitoring. Neonates, infants, and children: Treatment of hypertension or to achieve afterload reduction: 0. Treatment of extravasation: subcutaneous infiltration of the affected area with 0. Phentolamine should be used with addi- tional care in patients with impairment of renal function, gastritis, peptic ulcer disease, or a history of arrhythmia or angina. Adverse Effects Cardiovascular: hypotension (mostly in patients with intravascular volume depletion), tachycardia, arrhythmias, shock, ischemic cardiac events Gastrointestinal: vomiting, nausea, abdominal pain, diarrhea, exacerba- tion of peptic ulcer Neuromuscular and skeletal: weakness Central nervous system: dizziness Other: flushing, nasal congestion Drug-Drug Interactions Vasoconstrictive and hypertensive effects of epinephrine and ephedrine are antagonized by phentolamine. Poisoning Information Similar to phenoxybenzamine, overdosage is suspected in cases of excessive tachycardia, shock, vomiting, and dizziness (symptoms of sympathetic nervous system blockade and of increased circulating epine- phrine). Treatment of overdosage consists of the following: ● Drug withdrawal ● Recumbent position with leg elevation ● I. Nevertheless, epinephrine is contraindicated, because epinephrine stimulates both α- and β-receptors, and because α-receptors are blocked, epinephrine may produce further hypotension. Effects of adrenergic antagonists on cocaine-induced changes in respiratory function. Phentolamine as a treatment for poor mixing in transposition of the great arteries with adequate intra atrial communication. Dopaminergic Receptor Agonist: Fenoldapam Indication Treatment of significant systemic hypertension. In addition, rebound hypertension has not occurred after discontinuation of fenoldopam administered via continuous infusion. Through its selective receptor binding, fenoldopam reduces systemic blood pressure by decreasing peripheral vascular resistance and improves renal blood flow and diuresis. It is metab- olized in the liver to multiple metabolites, which may have some activity Elimination: 80% is excreted in the urine and 20% is excreted in feces Monitoring Parameters Blood pressure, heart rate, electrocardiogram, and renal and liver function tests. Adverse Effects Cardiovascular: angina, flattening of T-waves (asymptomatic)2, atrial fibrillation, atrial flutter, chest pain, edema, hypotension, tachycardia Central nervous system: headache, dizziness3 Gastrointestinal: diarrhea, nausea, vomiting, dry mouth Ophthalmological: increased intraocular pressure, blurred vision Hepatic: increased portal pressure in patients with cirrhosis Drug-Drug Interactions β-blockers increase the risk of hypotension, and acetaminophen may increase fenoldopam levels by 30 to 70%. Fenoldopam: a new dopamine agonist for the treatment of hypertensive urgencies and emergencies. Selective dopamine-1 agonist therapy in severe hypertension: effects of intravenous fenoldopam. Comparative acute blood pressure reduction from intravenous fenoldopam mesylate versus sodium nitroprusside in severe systemic hypertension. Congenital heart defects that create ductal-dependent circulations include pulmonary atresia, critical pulmonary stenosis, tricuspid atresia, tetralogy of Fallot and pulmonary atresia without major aortopulmonary collaterals, transposition of the great arteries, hypoplas- tic left heart syndrome, critical aortic stenosis, critical coarctation of the aorta, and interrupted aortic arch. Patients with severe pulmonary hypertension that is refractory to pulmonary antihypertensive drugs may benefit from a prostaglandin E1 infusion. This drug will maintain patency of the ductus arteriosus, which may decompress the pulmonary circulation while maintaining an adequate systemic cardiac output, albeit at the expense of systemic oxygen desaturation. Mechanism of Action Prostaglandin E1 causes vasodilation by exerting direct effects on vascular and ductus arteriosus smooth muscle. Patients receiving an infusion for longer than 5 days should be monitored for the devel- opment of gastric outlet obstruction.