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Rang and Dales. Ch 14. Anti-inflammatory and

immunosuppressant drugs (t/m237)

Non steroidal anti-inflammatory drugs.

Pharmacological actions.Three main therapeutic effects are:- An anti-inflammatory effect;- An analgesic effect;- An antipyretic effect;

In addition all NSAIDs share the same types of mechanism-based side effects:- gastric irritation;- An effect on renal blood flow in the compromised kidney;- Tendency to prolong bleeding;- Increased likelihood of thrombotic events.Cox-1 in a constitutive enzyme, involved in tissue homeostasis, responsible for theproduction of prostaglandins. COX-2 is induced in inflammatory cells

Antipyretic effect.Temperature is regulated by a centre in the hypthalamus that controls the balancebetween heat loss and heat producition. NSAIDs reset the thermostat. Normal bodytemperature in humans is not effected by NSAIDs. They exert their antipyretic actionlargely through inhibition of prostaglandin production in the hypothalamus. Interleukin-1releases prostaglandins in the central nervous system, where they elevate thehypothalamic set point for temperature control, thus causing fever. NSAIDs prevent this.

Analgesic effect.Effective against mild or moderate pain, especially that arising from inflammation or tissuedamage. Decreased prostaglandin generation means less sensitisation of nociceptive nerveendings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine.

Anti-inflammatory effect.The decrease in prostaglandin E2 and prostacyclin reduces:- Vasodilatation;- Oedema;

- Pain;

Unwanted effects.- Dyspepsia, nausea and vomiting: gastric damage may occur in chronic users, with risk ofhaemorrhage. The cause is suppression of gastro protective prostaglandins in the gastricmucosa.- Skin reactions;- Reversible renal insufficiency. Seen mainly in individuals with compromised renal functionwhen the compensatory prostaglandin E2-mediated vasodilatation is inhibited;- Analgesic-associated nephropathy. Can occur following long-continued high dose ofNSAIDs and is often irriversible;- Liver disorders , bone marrow depression. Uncommon.- Bronchospasm.

Aspirin.

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Act by irreversibly inactivating both COX-1 and COX-2. In addition to its inflammatoryactions, aspirin inhibits platelet aggregation. It is give orally and is rapidly absorbed; 75% ismetabolised 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. Itis 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-benzoquinoneimine. If not inactivated by conjugation with glutathione, this compound reacts with cellproteins and kills the cell.

Ch.22. Haemopoietic system.

1.1. Haemopoietic system.

Types of anemia.Anemia is defined as a reduced concentration of haemoglobin in the blood. Commonestcause is blood loss related to menstruation and child bearing.- Hypochromic, microcytic anemia (small red cells with low haemoglobin; caused by irondeficiency);- Macrocytic anaemia (large red cells, few in number);- Normochromic normocytic anemia (fewer normal-sized red cells, each with a normalhaemoglobin content);- Mixed pictures.This leads to more precised diagnotic groupings;- Deficiency of nutrients, iron/folic acid&vitamin B12/pyridoxine, vitamin C;

- Depression of the bone marrow, caused by radiation/toxins;- Excessive destruction of red cells.

1.2. Haematinic agents.Biological role:- Ability to exist in several oxidation states;- Ability to form stable coordination complexes.65/55% circulates in blood as haemoglobin. About one-half of the remainder is stored in theliver, spleen and bone marrow, chiefly as ferritin and haemosiderin. Heam group can carryone oxygen molecule, which is bound reversibly Fe2+ and to a histadine residue in theglobin chain.

Iron turnover and balance.5mg for men, and 15mg for menstruating women. There is no mechanism whereby ironexcretion is regulated, the absorptive mechanism has a central role in iron balance as it isthe sole mechanism by which body iron is controlled. The site of absorption is theduodenum and upper jejunum, and absorption is a two stage process involving first a rapiduptake across the brush border and then transfer into the plasma from the interior of theepithelial cells. Second stage is energy dependent. Iron is carried in the plasma bound totransferrin. Plasma contains 4mg of iron at any one time. Most of the iron that enters theplasma is derived from mononuclear phagocytes, following the degradation of time-expirederythrocytes. Intestinal absorption and mobilisation of iron from storage depots contributeonly small amounts. Soluble ferritin and insoluble haemosiderin. Ferritin is found in all cells,in the liver, spleen and bone marrow. It is also present in plasma. The precursor isapoferritin, it takes up ferrous iron, oxidises it and deposits the ferric iron in its core. The

lifespan of this protein is only a few days.

Administration.

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Main one is via ferrous sulfate, element iron content of 200ug/mg. Parenteral iron can begiven in individuals who are not able to absorb oral iron because of malabsorptionsyndromes. It is also used for patients who do not tolerate oral preparations, and patientswith chronic renal failure receiving treatment with erythropoietin. Preparations then usedare iron-dextran and iron-sucrose

Unwanted effects.They are dose-related and include nausea, abdominal cramps and diarrhoea. Parenteraliron can cause anaphylactoid reactions.- Acute iron toxicity: after ingestion of large quantities of iron salts. Result in severenecrotising gastritis with vomiting, haemorrhage and diarrhoea.- Chronic iron toxicity: caused by conditions other than ingestion of iron salts. Treatment ofacute 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 preventits absorption. Deferiprone, an orally absorbed iron chelator, is an alternative treatment foriron 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 folatedeficiency , 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.gsickle cell).Folic acid consists of a pteridine ring, p-aminobenzoic acid and glutamate residue. There isactive uptake into cells and reduction to FH4 by dihydrofolate reductase; extra glutamatesare then added. Folate polyglutamate is a cofactor in the synthesis of purines andpyrimidines.

Vitamin b12(hydroxocobalamin) is used for treatment of pernicous anemia and othercauses of vitamin B12 deficiency. Prophylactically after surgical operations that remove thesite of production (stomach) of intrinsic factor or of vitamin B12 (ileum). Vitamin B12 isstored in the liver. It is required for: Conversion of methyl-FH4 (inactive form of FH4) , is acofactor in the synthesis of purines and pyrimidines and isomeristaion of methylmalonyl-CoA to succinyl-CoA.

1.3. Haemopoietic growth factors.

EPO.

Erythropoietin regulates the red cell line, and the signal for its production is blood lossand/or low tissue oxygen tension. It is produced in juxtatubular cells in the kidney and alsoin macrophages; to stimulate committed erythroid progenitor cells to proliferate andgenerate erythrocytes.

It is give intravenously (fastest response), subcutaneously (greatest response),intraperitoneally. Can cause transient flu-like symptoms, hypertension, iron deficiency andincreased blood viscosity.

Colony-stimulating factors/CSFs.They stimulate the formation of maturing colonies of leucocytes in semisolid medium invitro. 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;

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- Expand the number of harvested progenitor cells ex vivo before reinfusing them;

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- For persistent neutropenia in advanced HIV infection;- In aplastic anemia.

Ch. 25. The gastrointestinal tract.1.1. Innervation and hormones of the gastrointestinal tract.Neuronal control.The myenteric plexus (Auerbachs plexus) between the outer, longitudinal and middle,circular muscle layers, and the submucous plezus (Meissners plexus) on the lumenal sideof the circular muscle layer. Their ganglion cells receive preganglionic parasympatheticfibres from the vagus, which are mostly cholinergic and excitatory. Incoming sympatheticfibres are largely postganglionic.

Hormonal control.The endocrine secretions are mainly peptidic in nature and are synthesised by endocrine

cells in the mucosa. They include gastrin and cholecystokinin. The paracrine secretionsinclude regulatory peptides released from special cells found throughout the wall.

1.2 Gastric secretion.The principal exocrine secretions by the chief or peptic cells, and hydrochloric acid (HCL)and intrinsic factor secreted by the parietal or oxyntic cells. Prostaglandins stimulate thesecretion of both mucus and bicarbonate, creating a gel-like protective barrier thatmaintains the mucosal surface at pH of 6-7.

Gastrin.Peptide hormone synthesised in endocrine cells of themucosa of the gastric antrum and duodenum, andsecreted in to the portal blood. Its main action isstimulation of the secretion of acid by the parietal cells.Gastrin also indirectly increases pepsinogen secretion,stimulates blood flow and increases gastric motility.

Acetylcholine.Released from neurons and stimulates specificmuscarinic receptors on the surface of the parietal cellsand on the surface of histamine-containing cells.

Histamine.Within the stomach, mast cells lying close to the parietal cells release a steady basalrelease of histamine. Hormone acts on parietal cells H2 receptors, which are responsive to

histamine concentrations that are below the threshold required for vascular H2 receptoractivation.

A illustration of the secretion of hydrochloric acid by gastric parietal cells (plaatje).Secretion involves a proton pump (p), which is an H+/K+ ATPase, a symport carrier (C) forK+ 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 Pyloriand 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 partlydirectly and partly indirectly by releasing histamine (two-cell hypothesis). AA, arachidonic

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a proton pump (p), which is an H+/K+ ATPase, a symport carrier (C) for K+ and Cl- , and anantiport (A), which exchanges CL- and HCO3-. An additional Na+/H+ antiport situated atthe interface with the plasma may also have a role (not shown).

The genesis of peptic ulcers invovles: infection of gastric mucosa with Helicobacter Pyloriand 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 partlydirectly and partly indirectly by releasing histamine (two-cell hypothesis). AA, arachidonicacid; AcH, acetylcholine, C, symport carrier for K+/Cl-; Gr, gastrin receptor; H2R, histamineH2 receptor; Hist, histamine; MC, mast cell-like histamine-secreting cell; MR, muscarinereceptor; 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 oftherapy 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 acidsecretion. They directly neutralise acid, thus raising the gastric pH. They can producehealing of duodenal ulcers but are less effective for gastric ulcers.- Magnesium hydroxide: is an insoluble powder that forms magnesium chloride in thestomach.- Magnesium trisilicate: insoluble powder that reacts slowly with the gastric juices, has aprolonged 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 aftercessation of treatment. Drugs used are ranitidine, nizatidine and famotidine. Unwantedeffects are rare. Diarrhoea, dizziness, muscle pains, alopecia, transient rashes andhypergastrinaemia have been reported. Cimetidine sometimes causes gynaecomastia inmen and also inhibits cp450.

Proton pump inhibitors.

Omeprazole, which irreversibly inhibits the H/K ATPase. Drug is weak base and accumulatesin 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 ascapsules containing enteric-coated granules. It is absorbed and, from blood, passes into theparietal cells and then into the canaliculi. A single daily dose affects acid secretion for 2-3days, 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 theantibacterials 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 onthe bacillus. Small amount of bismuth that is actually absorbed is excreted in the urine.

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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 withmucus, an action that is thought to decrease the degradation of mucus by pepsin and tolimit the diffusion of H+. Given orally. About 30% is still present in the stomach 3 hoursafter administration. Reduces the absorption of a number of other drugs, including

fluoroquinolone antibiotics. Unwanted effects are few , the most common beingconstipation.

Misoprostol: Protective action in the gastrointestinal tract. Given orally and is used topromote healing of ulcers or to prevent the gastric damage that can occur with chronic useof NSAIDs. Direct action on the parietal cell, inhibiting the basal secretion of gastric acid.Unwanted effects include diarrhoea, and abdominal cramps; uterine contractions can alsooccur.

The reflex mechanism of vomiting.Emetic stimuli include: chemicals or drugs in blood or intestine, neuronal input fromgastrointestinal tract, labyrinth and CNS. Pathways and mediators include: Impulses fromchemoreceptor trigger zone and varios other CNS centres relayed to the vomiting centre.

Chemical transmitters such as histamine, acetylcholine, dopamine and 5-hydroxytryptamine. Antiemetic drugs include: H1 receptor antagonists, muscarinantagnosts, 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 brokendown by the normal processes of digestion in the upper tract. They form a bulky hydratedmass in the gut lumen promoting peristalsis and improving faecal consistency. May takeseveral 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 ofthe 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 stimulantlaxative.

Stimulant laxatives: Act mainly by increasing electrolyte and hence water secretion by themucosa, and also by increasing peristalsis. Bisacodyl may be given by mouth but is oftengive by suppository. Senna and dantron are anthroquinone laxatives. The active principledirectly stimulates the myenteric plexus, resulting in increased peristalsis and thusdefecation.

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 orbudesonide, given orally.

Aminosalicylates: Glucocorticoids are not ideal for the long-term treatment (because oftheir side-effects). Maintenance of remission is generally achieved using theaminosalicylates.

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 isobscure.