By: Z. Arakos, M.B. B.CH. B.A.O., M.B.B.Ch., Ph.D.
Co-Director, Duquesne University College of Osteopathic Medicine
Tolerance and dependence-With frequently repeated therapeutic doses of morphine or its surrogates cholesterol vs medication cheap zocor 5mg otc, there is a gradual loss in effectiveness; this loss of effectiveness is termed tolerance foods to lower cholesterol & blood pressure discount generic zocor canada. Physical dependence is defined as a characteristic withdrawal or abstinence syndrome when a drug is stopped or an antagonist is administered (see also Chapter 32) cholesterol jaki powinien byc zocor 5mg. The mechanism of development of opioid tolerance and physical dependence is poorly understood cholesterol medication before blood test cheap zocor online mastercard, but persistent activation of receptors such as occurs with the treatment of severe chronic pain appears to play a primary role in its induction and maintenance. Although this process is associated with tolerance, it is not sufficient to explain it. A second hypothesis for the development of opioid tolerance and dependence is based on the concept of receptor recycling. Normally, activation of receptors by endogenous ligands results in receptor endocytosis followed by resensitization and recycling of the receptor to the plasma membrane (see Chapter 2). However, using genetically modified mice, research now shows that the failure of morphine to induce endocytosis of the -opioid receptor is an important component of tolerance and dependence. In further support of this idea, methadone, a -receptor agonist used for the treatment of opioid tolerance and dependence, induces receptor endocytosis. This suggests that maintenance of normal sensitivity of receptors requires reactivation by endocytosis and recycling. Under this hypothesis, tolerance results from a dysfunction of structural interactions between the receptor and G proteins, second-messenger systems, and their target ion channels. Uncoupling and recoupling of receptor function is likely linked to receptor recycling. Opioid-induced hyperalgesia-In addition to the development of tolerance, persistent administration of opioid analgesics can increase the sensation of pain, resulting in a state of hyperalgesia. This phenomenon can be produced with several opioid analgesics, including morphine, fentanyl, and remifentanil. However, chronic pain (lasting months to years) and especially pain arising from neuropathic causes are not very satisfactorily managed with opioids. It is now known that in chronic pain, receptors on sensory nerve terminals in the periphery contribute to increased excitability of these sensory endings (peripheral sensitization). The hyperexcitable sensory neuron bombards the spinal cord, leading to increased excitability and synaptic alterations in the dorsal horn (central sensitization). Such changes are likely important contributors to chronic inflammatory and neuropathic pain states. In the effort to discover better analgesic drugs for chronic pain, renewed attention is being paid to the molecular basis of peripheral sensory transduction. Lidocaine and mexiletine, which are useful in some chronic pain states, may act by blocking this class of channels. Because of the importance of their peripheral sites of action, therapeutic strategies that deliver agents that block peripheral pain transduction or transmission have been introduced in the form of transdermal patches and balms. Ziconotide, a blocker of voltage-gated N-type calcium channels, is approved for intrathecal analgesia in patients with refractory chronic pain. Ziconotide is a synthetic peptide related to the marine snail toxin -conotoxin, which selectively blocks N-type calcium channels. However, ketamine infused at very small doses improves analgesia and can reduce opioid requirements under conditions of opioid tolerance, eg, after major abdominal and spinal surgery. Nicotine itself and certain nicotine analogs cause analgesia, and their use for postoperative analgesia is under investigation. As our understanding of peripheral and central pain transduction improves, additional therapeutic targets and strategies will become available. Combined with our present knowledge of opioid analgesics, a "multimodal" approach to pain therapy is emerging. Another benefit of multimodal analgesia is reduced opioid requirements with fewer adverse effects. Opioid analgesics are unique in that they can reduce both aspects of the pain experience. In contrast, nonsteroidal anti-inflammatory analgesic drugs, eg, ibuprofen, have no significant effect on the emotional aspects of pain. Euphoria-Typically, patients or intravenous drug users who receive intravenous morphine experience a pleasant floating sensation with lessened anxiety and distress. However, dysphoria, an unpleasant state characterized by restlessness and malaise, may also occur. Moderate Bradycardia Minimal or None Miosis Constipation Convulsions High Analgesia Euphoria, dysphoria Mental clouding Sedation Respiratory depression Antidiuresis Nausea and vomiting Cough suppression f. This action, which can be blocked by opioid antagonists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine. It was originally believed that truncal rigidity involved a spinal cord action of these drugs, but a supraspinal action is likely. Truncal rigidity reduces thoracic compliance and thus interferes with ventilation. The effect is most apparent when high doses of the highly lipid-soluble opioids (eg, fentanyl, sufentanil, alfentanil, remifentanil) are rapidly administered intravenously. Truncal rigidity may be overcome by administration of an opioid antagonist, which of course will also antagonize the analgesic action of the opioid. Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents.
Anemia cholesterol medications zocor 40mg with visa, a deficiency in oxygen-carrying erythrocytes cholesterol young living buy 5mg zocor fast delivery, is the most common deficiency and several forms are easily treated cholesterol in shrimp good or bad discount zocor 10 mg on-line. Sickle cell anemia cholesterol medication and viagra buy genuine zocor on-line, a condition resulting from a genetic alteration in the hemoglobin molecule, is common but is not easily treated. Thrombocytopenia and neutropenia are not rare, and some forms are amenable to drug therapy. In this chapter, we first consider treatment of anemia due to deficiency of iron, vitamin B12, or folic acid and then turn to the medical use of hematopoietic growth factors to combat anemia, thrombocytopenia, and neutropenia, and to support stem cell transplantation. Iron forms the nucleus of the iron-porphyrin heme ring, which together with globin chains forms hemoglobin. Hemoglobin reversibly binds oxygen and provides the critical mechanism for oxygen delivery from the lungs to other tissues. In the absence of adequate iron, small erythrocytes with insufficient hemoglobin are formed, giving rise to microcytic hypochromic anemia. Ironcontaining heme is also an essential component of myoglobin, cytochromes, and other proteins with diverse biologic functions. A peptide called hepcidin, produced primarily by liver cells, serves as a key central regulator of the system. Nearly all of the iron used to support hematopoiesis is reclaimed from catalysis of the hemoglobin in senescent or damaged erythrocytes. Normally, only a small amount of iron is lost from the body each day, so dietary requirements are small and easily fulfilled by the iron available in a wide variety of foods. Like other forms of chronic anemia, iron deficiency anemia leads to pallor, fatigue, dizziness, exertional dyspnea, and other generalized symptoms of tissue hypoxia. The cardiovascular adaptations to chronic anemia-tachycardia, increased cardiac output, Sickle Cell Disease and Hydroxyurea Sickle cell disease is an important genetic cause of hemolytic anemia, a form of anemia due to increased erythrocyte destruction, instead of the reduced mature erythrocyte production seen with iron, folic acid, and vitamin B12 deficiency. Patients with sickle cell disease are homozygous for the aberrant -hemoglobin S (HbS) allele (substitution of valine for glutamic acid at amino acid 6 of -globin) or heterozygous for HbS and a second mutated -hemoglobin gene such as hemoglobin C (HbC) or -thalassemia. Sickle cell disease has an increased prevalence in individuals of African descent because the heterozygous trait confers resistance to malaria. Instead, the primary problem is that deoxygenated HbS chains form polymeric structures that dramatically change erythrocyte shape, reduce deformability, and elicit membrane permeability changes that further promote hemoglobin polymerization. Abnormal erythrocytes aggregate in the microvasculature-where oxygen tension is low and hemoglobin is deoxygenated-and cause veno-occlusive damage. In the musculoskeletal system, this results in characteristic, extremely severe bone and joint pain. Damage to the spleen increases the risk of infection, particularly by encapsulated bacteria such as Streptococcus pneumoniae. In the pulmonary system, there is an increased risk of infection and, in adults, an increase in embolism and pulmonary hypertension. Supportive treatment includes analgesics, antibiotics, pneumococcal vaccination, and blood transfusions. In addition, the cancer chemotherapeutic drug hydroxyurea (hydroxycarbamide) reduces veno-occlusive events. It is approved in the United States for treatment of adults with recurrent sickle cell crises and approved in Europe in adults and children with recurrent vaso-occlusive events. As an anticancer drug used in the treatment of chronic and acute myelogenous leukemia, hydroxyurea inhibits ribonucleotide reductase and thereby depletes deoxynucleoside triphosphate and arrests cells in the S phase of the cell cycle (see Chapter 54). In the treatment of sickle cell disease, hydroxyurea acts through poorly defined pathways to increase the production of fetal hemoglobin (HbF), which interferes with the polymerization of HbS. Clinical trials have shown that hydroxyurea decreases painful crises in adults and children with severe sickle cell disease. Its adverse effects include hematopoietic depression, gastrointestinal effects, and teratogenicity in pregnant women. The transferrin-iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes and is internalized. After release of iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Hepatocytes use several mechanisms to take up iron and store the iron as ferritin. High hepatic iron stores increase hepcidin synthesis, and hepcidin inhibits ferroportin; low hepatocyte iron and increased erythroferrone inhibits hepcidin and enhances iron absorption via ferroportin. Iron is absorbed in the duodenum and proximal jejunum, although the more distal small intestine can absorb iron if necessary. Iron absorption increases in response to low iron stores or increased iron requirements. Iron in other foods, especially vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption. Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferrireductase to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells. Since the ferritin present in serum is in equilibrium with storage ferritin in reticuloendothelial tissues, the serum ferritin level can be used to estimate total body iron stores. Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat.
It is particularly interesting that unlike other diuretics that act upstream of the collecting tubules cholesterol levels for age buy zocor 5 mg online, adenosine antagonists do not cause wasting of K+ cholesterol of 150 trusted zocor 5 mg. They were discovered in 1937 when it was found that bacteriostatic sulfonamides caused an alkaline diuresis and hyperchloremic metabolic acidosis cholesterol levels chart uk us 5mg zocor with visa. With the development of newer agents cholesterol levels measurement purchase zocor 10 mg mastercard, carbonic anhydrase inhibitors are now rarely used as diuretics, but they still have several specific applications that are discussed below. Pharmacokinetics the carbonic anhydrase inhibitors are well absorbed after oral - administration. Glaucoma the reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure. Topically active agents, which reduce intraocular pressure without producing renal or systemic effects, are available (dorzolamide, brinzolamide). Urinary Alkalinization Uric acid and cystine are relatively insoluble and may form stones in acidic urine. As a result, these agents have proved to be of limited utility for this indication. Metabolic Alkalosis Metabolic alkalosis is generally treated by correction of abnormalities in total body K+, intravascular volume, or mineralocorticoid levels. However, when the alkalosis is due to excessive use of diuretics in patients with severe heart failure, replacement of intravascular volume may be contraindicated. In these cases, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload. Acetazolamide can also be used to rapidly correct the metabolic alkalosis that may appear following the correction of respiratory acidosis. Acute Mountain Sickness Weakness, dizziness, insomnia, headache, and nausea can occur in mountain travelers who rapidly ascend above 3000 m. In more serious cases, rapidly progressing pulmonary or cerebral edema can be life-threatening. Other Uses Carbonic anhydrase inhibitors have been used as adjuvants in the treatment of epilepsy and in some forms of hypokalemic periodic paralysis. Although we have known about the proximal tubule sodium/glucose cotransporter for many years, the inhibitors of this transport channel were developed only recently. Renal Stones Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic anhydrase. Renal excretion of solubilizing factors (eg, citrate) may also decline with chronic use. Calcium phosphate salts are relatively insoluble at alkaline pH, which means that the potential for renal stone formation from these salts is enhanced. This effect can be counteracted by simultaneous administration of potassium chloride or a K+-sparing diuretic. Potassium wasting is theoretically a problem with any diuretic that increases Na+ delivery to the collecting tubule. In addition to potassium wasting, carbonic anhydrase inhibitors can lead to phosphorus wasting, and even symptomatic hypophosphatemia has been reported with these agents. Therefore, both serum potassium and serum phosphorus should be monitored in patients who are being treated chronically with these agents. Other Toxicities Drowsiness and paresthesias are common following large doses of acetazolamide. Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous system toxicity. Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur. Although the drug levels are higher with more severe renal failure, urinary glucose excretion would also decline as chronic kidney disease worsens. The drugs are not recommended in patients with more severe renal failure or advanced liver disease. For example, concomitant rifampin administration reduces the total exposure to dapagliflozin by 22%. Clinical Indications and Adverse Reactions Currently, the only indication for the use of these drugs is as third-line therapy for diabetes mellitus (see Chapter 41). In one study, ipragliflozin resulted in an increase in urine volume from day 1 to day 3. Both urine sodium and urine potassium excretion increased with the use of ipragliflozin, but the serum concentrations of both electrolytes remained stable. Thus, it is likely that at least part of the weight loss is due to the diuretic effect of the drugs. There is a sixfold increased incidence of genital fungal infection in women and a slightly higher risk of urinary tract infections (8. All of these agents have been shown to have no or minimal effects on serum electrolyte concentrations. Because of the large NaCl absorptive capacity of this segment and the fact that the diuretic action of these drugs is not limited by development of acidosis, as is the case with the carbonic anhydrase inhibitors, loop diuretics are the most efficacious diuretic agents currently available.
Binding of an agonist molecule by one of the two receptor sites only modestly increases the probability of channel opening; simultaneous binding of agonist by both of the receptor sites greatly enhances opening probability cholesterol ratio average buy zocor 5mg online. Nicotinic receptor activation causes depolarization of the nerve cell or neuromuscular end plate membrane cholesterol from shrimp purchase discount zocor on-line. Prolonged agonist occupancy of the nicotinic receptor abolishes the effector response; that is what causes cholesterol in eggs discount zocor 10 mg on line, the postganglionic neuron stops firing (ganglionic effect) cholesterol numbers chart uk buy zocor, and the skeletal muscle cell relaxes (neuromuscular end plate effect). Furthermore, the continued presence of the nicotinic agonist prevents electrical recovery of the postjunctional membrane. Thus, a state of "depolarizing blockade" occurs initially during persistent agonist occupancy of the receptor. Continued agonist occupancy is associated with return of membrane voltage to the resting level. The receptor becomes desensitized to agonist, and this state is refractory to reversal by other agonists. As described in Chapter 27, this effect can be exploited to produce muscle paralysis. The effects of nicotinic agonists are similarly predictable from knowledge of the physiology of the autonomic ganglia and skeletal muscle motor end plate. Eye-Muscarinic agonists instilled into the conjunctival sac cause contraction of the smooth muscle of the iris sphincter (resulting in miosis) and of the ciliary muscle (resulting in accommodation). As a result, the iris is pulled away from the angle of the anterior chamber, and the trabecular meshwork at the base of the ciliary muscle is opened. Both effects facilitate aqueous humor outflow into the canal of Schlemm, which drains the anterior chamber. Cardiovascular system-The primary cardiovascular effects of muscarinic agonists are reduction in peripheral vascular resistance and changes in heart rate. Larger doses of acetylcholine produce bradycardia and decrease atrioventricular node conduction velocity in addition to causing hypotension. Organ Eye Sphincter muscle of iris Ciliary muscle Heart Sinoatrial node Atria Response Contraction (miosis) Contraction for near vision (accommodation) Decrease in rate (negative chronotropy) Decrease in contractile strength (negative inotropy). Decrease in refractory period Decrease in conduction velocity (negative dromotropy). Constriction (high-dose direct effect) Contraction (bronchoconstriction) Secretion Increase Relaxation Stimulation Contraction Relaxation Secretion Atrioventricular node Ventricles Blood vessels Arteries, veins Lung Bronchial muscle Bronchial glands Gastrointestinal tract Motility Sphincters Secretion Urinary bladder Detrusor Trigone and sphincter Glands Sweat, salivary, lacrimal, nasopharyngeal 1 Only the direct effects are indicated; homeostatic responses to these direct actions may be important (see text). All these actions are mediated by M2 receptors and contribute to slowing the pacemaker rate. Effects (1) and (2) cause hyperpolarization, reduce action potential duration, and decrease the contractility of atrial and ventricular cells. Predictably, knockout of M2 receptors eliminates the bradycardic effect of vagal stimulation and the negative chronotropic effect of carbachol on sinoatrial rate. Muscarinic receptors that are present on postganglionic parasympathetic nerve terminals allow neurally released acetylcholine to inhibit its own secretion. The neuronal muscarinic receptors need not be the same subtype as found on effector cells. Therefore, the net effect on heart rate depends on local concentrations of the agonist in the heart and in the vessels and on the level of reflex responsiveness. Parasympathetic innervation of the ventricles is much less extensive than that of the atria; activation of ventricular muscarinic receptors causes much less direct physiologic effect than that seen in atria. However, the indirect effects of muscarinic agonists on ventricular function are clearly evident during sympathetic nerve stimulation because of muscarinic modulation of sympathetic effects ("accentuated antagonism"). In the intact organism, intravascular injection of muscarinic agonists produces marked vasodilation. However, earlier studies of isolated blood vessels often showed a contractile response to these agents. Isolated vessels prepared with the endothelium preserved consistently reproduce the vasodilation seen in the intact organism. This effect was eliminated in the absence of endothelium, and acetylcholine, at concentrations greater than 10-7 M, then caused contraction. Parasympathetic nerves can regulate arteriolar tone in vascular beds in thoracic and abdominal visceral organs. Damage to the endothelium, as occurs with atherosclerosis, eliminates this action, and acetylcholine is then able to contract arterial smooth muscle and produce vasoconstriction. Skeletal muscle receives sympathetic cholinergic vasodilator nerves, but the view that acetylcholine causes vasodilation in this vascular bed has not been verified experimentally. However, this vascular bed responds to exogenous choline esters because of the presence of M3 receptors on endothelial and smooth muscle cells. The cardiovascular effects of all the choline esters are similar to those of acetylcholine-the main difference being in their potency and duration of action. Because of the resistance of methacholine, carbachol, and bethanechol to acetylcholinesterase, lower doses given intravenously are sufficient to produce effects similar to those of acetylcholine, and the duration of action of these synthetic choline esters is longer. The cardiovascular effects of most of the cholinomimetic natural alkaloids and the synthetic analogs are also generally similar to those of acetylcholine.
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