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Intention tremor occurs in patients with a lesion of the brainstem or cerebellum cheap 100mg pletal with mastercard spasms due to redundant colon, especially when the superior cerebellar peduncle is involved; it may also occur as a manifestation of toxicity from alcohol or certain other drugs buy discount pletal 50mg online muscle relaxant medication over the counter. Chorea consists of irregular bupron sr 150 mg, unpredictable, involuntary muscle jerks that occur in different parts of the body and impair voluntary activity. In some instances, the proximal muscles of the limbs are most severely affected, and because the abnormal movements are then particularly violent, the term ballismus has been used to describe them. Chorea may be hereditary or may occur as a complication of a number of general medical disorders and of therapy with certain drugs. Abnormal movements may be slow and writhing in character (athetosis) and in some instances are so sustained that they are more properly regarded as abnormal postures (dystonia). Athetosis or dystonia may occur with perinatal brain damage, with focal or generalized cerebral lesions, as an acute complication of certain drugs, as an accompaniment of diverse neurologic disorders, or as an isolated inherited phenomenon of uncertain cause known as idiopathic torsion dystonia or dystonia musculorum deformans. Various genetic loci have been reported depending on the age of onset, mode of inheritance, and response to dopaminergic therapy. Tics are sudden coordinated abnormal movements that tend to occur repetitively, particularly about the face and head, especially in children, and can be suppressed voluntarily for short periods of time. Gilles de la Tourette’s syndrome is characterized by chronic multiple tics; its pharmacologic management is discussed at the end of this chapter. The basic circuitry of the basal ganglia involves three interacting neuronal loops that include the cortex and thalamus as well as the basal ganglia themselves (Figure 28–1). However, the precise function of these anatomic structures is not yet fully understood, and it is not possible to relate individual symptoms to involvement at specific sites. In Parkinson’s disease, there is degeneration of the pars compacta of the substantia nigra, leading to overactivity in the indirect pathway (red) and increased glutamatergic activity by the subthalamic nucleus. Other non-motor symptoms—which are receiving increasing attention—are affective disorders (anxiety or depression), personality changes, abnormalities of autonomic function (sphincter or sexual functions; choking; sweating abnormalities; and disturbances of blood pressure regulation), sleep disorders, and sensory complaints or pain. The disease is generally progressive, leading to increasing disability unless effective treatment is provided. Pathogenesis The pathogenesis of parkinsonism seems to relate to a combination of impaired degradation of proteins, intracellular protein accumulation and aggregation, oxidative stress, mitochondrial damage, inflammatory cascades, and apoptosis. Studies in twins suggest that genetic factors are important, especially when the disease occurs in patients under age 50. Mutations of the α-synuclein gene at 4q21 or duplication and triplication of the normal synuclein gene are associated with Parkinson’s disease, which is now widely recognized as a synucleinopathy. Epidemiologic studies reveal that cigarette smoking, coffee, anti-inflammatory drug use, and high serum uric acid levels are protective, whereas the incidence of the disease is increased in those working in teaching, health care, or farming, and in those with lead or manganese exposure or with vitamin D deficiency. The finding of Lewy bodies (intracellular inclusion bodies containing α-synuclein) in fetal dopaminergic cells transplanted into the brain of parkinsonian patients some years previously has provided some support for suggestions that Parkinson’s disease may represent a prion disease. Staining for α-synuclein has revealed that pathology is more widespread than previously recognized, developing initially in the olfactory nucleus and lower brainstem (stage 1 of Braak scale), then the higher brainstem (stage 2), the substantia nigra (stage 3), the mesocortex and thalamus (stage 4), and finally the entire neocortex (stage 5). The normally high concentration of dopamine in the basal ganglia of the brain is reduced in parkinsonism, and pharmacologic attempts to restore dopaminergic activity with levodopa and dopamine agonists alleviate many of the motor features of the disorder.
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These in- the most common means of parenteral drug administra- clude (1) capillary permeability buy pletal 50 mg lowest price muscle relaxant herbs, (2) blood ﬂow–tissue tion buy pletal 50mg on line muscle relaxant chlorzoxazone. Drug absorption (6) the permeability characteristics of speciﬁc tissue from intramuscular and subcutaneous sites depends on membranes generic ketoconazole cream 15gm with mastercard. The rate of Advantages of the intramuscular and subcutaneous passage of drugs across capillary walls can be inﬂuenced routes include an increased reliability and precision in by agents that affect capillary permeability (e. These compartments include plasma Intravenous Administration water (approximately 10 L), interstitial ﬂuid (10 L), and the intracellular ﬂuid (20 L). Total extracellular water is Intravenous drug administration ensures immediate the sum of the plasma and the interstitial water. Factors pharmacological response; problems of absorption are such as sex, age, edema, pregnancy, and body fat can in- circumvented because the entire quantity of drug enters ﬂuence the volume of these various compartments. This route is also useful for The rate at which an equilibrium concentration of a compounds that are poorly or erratically absorbed, are drug is reached in the extracellular ﬂuid of a particular extremely irritating to tissues, or are rapidly metabo- tissue will depend on the tissue’s perfusion rate; the lized before or during their absorption from other sites. The pharmacokinetic concept of vol- A serious disadvantage of intravenous drug admin- ume of distribution (a derived parameter that relates istration becomes clearly apparent when an overdose the amount of drug in the body to the plasma concen- is inadvertently given: Neither can the drug be re- tration) is discussed more fully in Chapter 5. The extent of this binding will inﬂu- Albumin ence the drug’s distribution and rate of elimination be- cause only the unbound drug can diffuse through the Of the plasma proteins, the most important contributor capillary wall, produce its systemic effects, be metabo- to drug binding is albumin. Many highly al- ion and in dynamic equilibrium, according to the law of bumin-bound drugs are poorly soluble in water, and for mass action. Since only the unbound (or free) drug dif- such drugs, binding to hydrophobic sites on albumin is fuses through the capillary walls, extensive binding may often important. The magnitude of of an acidic drug are bound per albumin molecule, this decrease is directly proportional to the fraction of whereas basic, positively charged drugs are more drug bound to plasma protein. As drug nonspeciﬁc; that is, many drugs may interact with the dosage increases, eventually the binding capacity of the same binding site. A drug with a higher afﬁnity may dis- protein becomes saturated and any additional drug will place a drug with weaker afﬁnity. However, in practice, changes in protein bind- culation, thereby slowing the rate of transfer across the ing result in clinically signiﬁcant effects for only a lim- capillary. Thus, binding poalbuminemia, uremia, hyperbilirubinemia) have been does not prevent the drug from reaching its site of ac- associated with changes in plasma protein binding of tion but only retards the rate at which this occurs. For example, in uremic patients the plasma pro- Extensive plasma protein binding may prolong drug tein binding of certain acidic drugs (e. Drugs that are Lipoproteins highly bound to plasma proteins may distribute less widely because they remain trapped in the peripheral vas- Drugs that bind to lipoproteins do so by dissolving in culature, since the plasma proteins themselves cannot tra- the lipid portion of the lipoprotein core. The lung receives the entire cardiac out- the drug ﬁrst binding to a number of sites on the protein put; therefore, drug distribution into it is very moiety and then dissolving in the lipid phase.
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Symptoms are 118 Chapter 3 caused by decreased blood fow to the heart muscle 116 The answer is C: Reduction of dietary salt to 10 g/d pletal 50 mg with mastercard spasms in stomach. Prinzmetal angina generally responds promptly fat buy generic pletal pills muscle relaxant rub, cholesterol cheap naprosyn 250 mg free shipping, and sodium; salt—reduce dietary so- to coronary vasodilators, such as nitroglycerin and dium to no more than 2. High doses of or- ganic nitrates can also cause postural hypotension, 117 The answer is B: Fluid retention. Phosphodiesterase V dilation of resistance vessels (arterioles) but not of inhibitors such as sildenafl, tardenafl, and vardenafl capacitance vessels (venules). To preclude the tered orally for treatment of severe to malignant hy- dangerous hypotension that may occur, this combina- pertension that is refractory to other drugs. Ranolazine is indicated for the treatment of 118 The answer is C:A 55-year-old man with encephalopathy chronic angina and may be used alone or in combina- and blood pressure of 220/160 mm Hg. Hypertensive tion with other traditional therapies but is most often emergency is a rare but life-threatening situation in used as an option in patients with angina who have which the diastolic blood pressure is either greater failed all other antianginal therapies. It is not to be than 150 mm Hg (with systolic blood pressure greater used to treat an acute attack of angina. Administration of sodium nitroprusside will dermal nitroglycerin can sustain blood levels for as long worsen hypotension. Administration of so- mended that the patch be removed after 10 to 12 h to dium nitroprusside will worsen hypotension. Cardiovascular Pharmacology 119 For older (and black) patients, consider starting on a have the risks of catheterization. The best window for antithrombotics to be effective in cardiac choice antihypertensive agent for a 60-year-old black vessel recanalization is 2 to 6 h. Alteplase is approved for hypertension associated with preeclampsia typically the treatment of myocardial infarction, massive pul- does not warrant treatment. Reteplase is similar pregnancy because of possible fetal cyanide poisoning to alteplase and can be used as an alternative. Prazosin produces frst- tered within 3 h of the onset of stroke for maximal dose hypotension, presumably by blocking a1- effectiveness. It decreases the anemia means a decrease in total hemoglobin but with secretion of potassium in the urine. The net loop diuretics are most effective in removing large result of the action potential to this point is a net gain fuid volumes from the body and are the treatment of of sodium and loss of potassium. Medication A is nitro- (E) Spironolactone is a potassium-sparing diuretic glycerin and is the agent of choice in acute chest pain. Acetazolamide is used prophylactically for several (C) Medication C is isosorbide mononitrate and only Cardiovascular Pharmacology 121 has an extended-release formulation and is not suit- decrease constriction of blood vessels but would not able in this patient. This agent has an onset of action of 5 to frst choice for pregnant women with hypertension 10 min and a duration of action of 6 to 8 h.