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Act by irreversibly inactivating both COX-1 and COX-2. In addition to its inflammatory actions, aspirin inhibits platelet aggregation. It is give orally and is rapidly absorbed; 75% is metabolised by the liver. Unwanted effects involve: - With therapeutic doses: some gastric bleeding; - Large doses: dizziness, deafness and tinnitus; - toxic doses: uncompensated respiratory acidosis with metabolic acidosis may occur. Paracetamol. Has potent analgesic and antipyretic actions but rather weaker anti-inflammatory effects. It is give orally and metabolised in the liver. Toxic doses cause nausea and vomiting , then, after 24-48 hours potentially fatal liver damage by saturating normal conjugating enzymes, causing the drug to be converted by mixed function oxidases to N-acteyl-p-benzoquinone imine. If not inactivated by conjugation with glutathione, this compound reacts with cell proteins and kills the cell.
Main one is via ferrous sulfate, element iron content of 200ug/mg. Parenteral iron can be given in individuals who are not able to absorb oral iron because of malabsorption syndromes. It is also used for patients who do not tolerate oral preparations, and patients with chronic renal failure receiving treatment with erythropoietin. Preparations then used are iron-dextran and iron-sucrose Unwanted effects. They are dose-related and include nausea, abdominal cramps and diarrhoea. Parenteral iron can cause anaphylactoid reactions. - Acute iron toxicity: after ingestion of large quantities of iron salts. Result in severe necrotising gastritis with vomiting, haemorrhage and diarrhoea. - Chronic iron toxicity: caused by conditions other than ingestion of iron salts. Treatment of acute and chronic iron toxicity involves use of iron chelators such as desferrioxamine. Given intragastrically following acute overdose to bind iron in the bowel lumen and prevent its absorption. Deferiprone, an orally absorbed iron chelator, is an alternative treatment for iron overload in patients with thalassemia major who are unable to take desferrioaxmine. Folic acid and vitamin B12. Folic acid is used for the treatment of megaloblastic anaemia resulting from folate deficiency , which can be caused by: - Poor diet (common alcoholic individuals); - Malabsorption syndromes; - Drugs. Prophylactically in individuals at hazard from developing folate deficiency is important: - Pregnant women and before conception; - Premature infants; - Patients with severe chronic haemolytic aneamias, including haemoglobinopathies (.e.g sickle cell). Folic acid consists of a pteridine ring, p-aminobenzoic acid and glutamate residue. There is active uptake into cells and reduction to FH4 by dihydrofolate reductase; extra glutamates are then added. Folate polyglutamate is a cofactor in the synthesis of purines and pyrimidines. Vitamin b12(hydroxocobalamin) is used for treatment of pernicous anemia and other causes of vitamin B12 deficiency. Prophylactically after surgical operations that remove the site of production (stomach) of intrinsic factor or of vitamin B12 (ileum). Vitamin B12 is stored in the liver. It is required for: Conversion of methyl-FH4 (inactive form of FH4) , is a cofactor in the synthesis of purines and pyrimidines and isomeristaion of methylmalonylCoA to succinyl-CoA. 1.3. Haemopoietic growth factors. EPO. Erythropoietin regulates the red cell line, and the signal for its production is blood loss and/or low tissue oxygen tension. It is produced in juxtatubular cells in the kidney and also in macrophages; to stimulate committed erythroid progenitor cells to proliferate and generate erythrocytes. It is give intravenously (fastest response), subcutaneously (greatest response), intraperitoneally. Can cause transient flu-like symptoms, hypertension, iron deficiency and increased blood viscosity. Colony-stimulating factors/CSFs. They stimulate the formation of maturing colonies of leucocytes in semisolid medium in vitro. They are classified as cytokines. Granulocyte CSF is produced mainly by monocytes, fibroblasts and endothelial cells, and controls primarily the development of neutrophils. They are used for: - To reduce severity/duration of neutropenia induced by cytotoxic drugs; - To harvest progenitor cells;
- Expand the number of harvested progenitor cells ex vivo before reinfusing them;
a proton pump (p), which is an H+/K+ ATPase, a symport carrier (C) for K+ and Cl- , and an antiport (A), which exchanges CL- and HCO3-. An additional Na+/H+ antiport situated at the interface with the plasma may also have a role (not shown). The genesis of peptic ulcers invovles: infection of gastric mucosa with Helicobacter Pylori and an imbalance between the mucosal-damaging and the mucosal protecting agents. 1.3. Drugs used to inhibit or neutralise gastric acid secretion. Acetylcholine and gastrin act either directly on their receptors (one-cell hypothesis)or partly directly and partly indirectly by releasing histamine (two-cell hypothesis). AA, arachidonic acid; AcH, acetylcholine, C, symport carrier for K+/Cl-; Gr, gastrin receptor; H2R, histamine H2 receptor; Hist, histamine; MC, mast cell-like histamine-secreting cell; MR, muscarine receptor; P, proton pump H+/k+ ATPase; PGE2, prostaglandin E2.
Clinical use of agents affecting gastic acidity. - Histamine H2 receptor antagonists: Peptic ulcer, reflux oesophagitis; - Proton pump inhibitors (omeprazole): peptic ulcer, reflux oesophagitis, component of therapy for H. pylori infection; - Antacids : dyspepsia, symptomatic relief in peptic ulcer or oesophageal reflux; - Bismuth chelate: component of H.pylori infection treatment. Antacids. The simplest of all the therapies for treating the symptoms of excessive gastric acid secretion. They directly neutralise acid, thus raising the gastric pH. They can produce healing of duodenal ulcers but are less effective for gastric ulcers. - Magnesium hydroxide: is an insoluble powder that forms magnesium chloride in the stomach. - Magnesium trisilicate: insoluble powder that reacts slowly with the gastric juices, has a prolonged antacid effect. - Aluminium hydroxide gel: forms aluminium chloride in the stomach; reaches the intestine, the chloride is released and is reabsorbed. Effect continues for several hours. Histamine H2 receptor antagonists. Also promote healing of duodenal ulcers. However, relapses are likely to follow after cessation of treatment. Drugs used are ranitidine, nizatidine and famotidine. Unwanted effects are rare. Diarrhoea, dizziness, muscle pains, alopecia, transient rashes and hypergastrinaemia have been reported. Cimetidine sometimes causes gynaecomastia in men and also inhibits cp450. Proton pump inhibitors. Omeprazole, which irreversibly inhibits the H/K ATPase. Drug is weak base and accumulates in the acid environment of the canaliculi of the stimulated parietal cell where it is activated. Omeprazole is given orally, but as it degrades rapidly at low PH it is administered as capsules containing enteric-coated granules. It is absorbed and, from blood, passes into the parietal cells and then into the canaliculi. A single daily dose affects acid secretion for 2-3 days, because it accumulates in the canaliculi and inhibits H/K ATPase irreversibly. Treatment of H. pylori. Triple therapy usually comprises a proton pump inhibitor in combination with the antibacterials amoxicillin and metronidazole or clarithromycin. Drugs that protect the mucosa. Termed cytoprotective. Bismuth chelate: is used in combination regimens to treat H. pylori. It has toxic effects on the bacillus. Small amount of bismuth that is actually absorbed is excreted in the urine.
Unwanted effect include nausea and vomiting, and blackening of the tongue and feaces. Sucralfate: releases aluminium in the presence of acid. It can form complex gels with mucus, an action that is thought to decrease the degradation of mucus by pepsin and to limit the diffusion of H+. Given orally. About 30% is still present in the stomach 3 hours after administration. Reduces the absorption of a number of other drugs, including fluoroquinolone antibiotics. Unwanted effects are few , the most common being constipation. Misoprostol: Protective action in the gastrointestinal tract. Given orally and is used to promote healing of ulcers or to prevent the gastric damage that can occur with chronic use of NSAIDs. Direct action on the parietal cell, inhibiting the basal secretion of gastric acid. Unwanted effects include diarrhoea, and abdominal cramps; uterine contractions can also occur. The reflex mechanism of vomiting. Emetic stimuli include: chemicals or drugs in blood or intestine, neuronal input from gastrointestinal tract, labyrinth and CNS. Pathways and mediators include: Impulses from chemoreceptor trigger zone and varios other CNS centres relayed to the vomiting centre. Chemical transmitters such as histamine, acetylcholine, dopamine and 5hydroxytryptamine. Antiemetic drugs include: H1 receptor antagonists, muscarin antagnosts, cannabinoids etc. 1.4. Motility of gastrointestinal tract. Purgatives. Accelerate the passage of food. Bulk and osmotic laxatives: Bulk agents are polysaccharide polymers that are not broken down by the normal processes of digestion in the upper tract. They form a bulky hydrated mass in the gut lumen promoting peristalsis and improving faecal consistency. May take several days to work. Osmotic laxatives consist of poorly absorbed solutes and lactulose. By producing an osmotic load, these agents trap increased volumes of fluid in the lumen of the bowel, accelerating the transfer of the gut contents through the small intestine. Faecal softeners: Docusate sodium is a surface-active compound. It is also weak stimulant laxative. Stimulant laxatives: Act mainly by increasing electrolyte and hence water secretion by the mucosa, and also by increasing peristalsis. Bisacodyl may be given by mouth but is often give by suppository. Senna and dantron are anthroquinone laxatives. The active principle directly stimulates the myenteric plexus, resulting in increased peristalsis and thus defecation. 1.5 Drugs for chronic bowel diseas. Irritable bowel syndrome, ulcerative colitis and Crohns disease. Glucocorticoids: Are potent anti-inflammatory agents. Drugs of choice are prednisolone or budesonide, given orally. Aminosalicylates: Glucocorticoids are not ideal for the long-term treatment (because of their side-effects). Maintenance of remission is generally achieved using the aminosalicylates. Sulfasalazine: Is a combination of the sulfanomide sulfapyridine with 5-aminosalicylic acid. Latter forms the active moiety when it is released in the colon. Mechanism of action is obscure.