Pharmacology Review Questions – Week 7 (Case Studies)

Pharmacology Review Questions – Week 7 (Case Studies)

DRUGS AND LOCAL CHEMICAL MEDIATORS Sheila A Doggrell School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Gardens Point, GPO Box 2434, QLD 4001, Australia Phone +61 7 3870574 Fax +61 7 31381534 Email sheila.doggrell@qut.edu.au Reviewer required Key words: histamine, cytokines, drugs that modify, cyclooxygenase, lipooxygenase, action of eicosanoids, drugs that modify the actions of eicosanoids, 5- hydroxytryptamine (5-HT), nitric oxide, endothelin 10.1 Histamine and cytokines 10.1.1 Actions of histamine 10.1.2 Drugs that modify the actions of histamine 10.1.3 Cytokines 10.2 Eicosanoids 10.2.1 Cyclooxygenase (COX) and lipooxygenase system 10.2.2 Actions of eicosanoids 10.2.3 Drugs that modify the actions of eicosanoids 10.2.3.1 Inhibit phospholipase A2 10.2.3.2 Non-selective cyclooxygenase inhibitors 10.2.3.3 Selective COX-2 inhibitors 10.2.3.4 Agonists at prostaglandin receptors 10.2.3.5 Leukotriene receptor antagonists 10.3. 5-Hydroxtryptamine (serotonin), nitric oxide, and endothelin 10.3.1 5-HT and migraine 10.3.2 5-HT and the gastrointestinal tract 10.3.3 Nitric oxide and angina 10.3.4 Nitric oxide and erectile dysfunction 10.3.5 Endothelin and pulmonary hypertension LOCAL CHEMICAL MEDIATORS Cell-to-cell communication is the key to most processes in the body, and this cell-to-cell communication uses chemical mediators. Chemical mediators are classified into four groups: nervous, endocrine, paracrine, and autocrine (Table 10.1). Table 10.1 Chemical mediators (modified from Table 29.1 in Bullock S et al) Nerves secrete neurotransmitters that act over a short range, and have a relatively rapid action. The neurotransmitters in the peripheral nervous systems have already been discussed and drugs and the central nerve system will be discussed in future chapters. Endocrine glands secrete hormones into the blood, where they circulate until they find their target receptor. The actions of hormones are relatively prolonged. Various hormones are discussed further in Systematic pharmacology. The other groups of chemical mediators, paracrine and autocrine secretion, are involved in local actions. Paracrine secretions are of local hormones released into the circulation to have an effect on a neighbouring cell. These actions are relatively rapid. The local hormones to be discussed are the prostaglandins, nitric oxide and endothelin. Actually, some of the actions of the prostaglandins are autocrine, whereby the action is on the secreting cell. Histamine, 5-hydroxytryptamine (5-HT) and cytokines also have some autocrine activity. As there is overlap between the paracrine and autocrine actions of some chemical mediators, I prefer just to call the combination of local hormones and autocoids, local chemical mediators. In the following sections, some important local chemical mediators are discussed, and how drugs can modify the effects of these chemical mediators are considered. 10.1 Histamine and Cytokines The highest concentrations of histamine in the body are stored in mast cells, a cell found in connective tissue that contains granules of chemicals including histamine. In the periphery, histamine is an autocoid. The two best characterised effects of histamine are its major roles in allergy and in gastric secretion. Histamine is stored in secretory granules in mast cells, and basophils (circulating equivalent of mast cells). The highest levels of histamine are found in lungs, followed by the mucous membranes, skin, stomach, and central nervous system. Histamine is released from mast cells and basophils in tissue damage or in hypersensitivity reactions. Histamine H1- receptors mediate hypersensitivity, while histamine H2- receptors mediate gastric acid secretion. 10.1.2 Actions of histamine Histamine has a major role in Type 1 allergic reaction, which is the most common type of allergic reaction. Type 1 allergy can lead to anaphylactic reactions. Type I allergy is also known as immediate hypersensitivity reaction, and is often just called allergy. Allergy can be caused by a number of things including grass pollen, house dust mites, certain foods, animal fur…. Medicines that can cause allergy include aspirin, angiotensin converting enzyme inhibitors, and penicillin. With allergy, there is the release of contents of the mast cells and basophils. The contents of mast cells include histamine, eicosanoids, and cytokines. There local chemical mediators cause vasodilation, oedema, and inflammation. Sometimes allergy is limited to certain sites e.g. food allergies affect gastrointestinal tract. Whereas contact allergies may be limited to skin, where allergy is manifest as urticaria (hives) and atopic dermatitis (itching + raised red rash). Allergy to inhalants e.g. grass pollen, may be limited to the respiratory system and manifest as rhinitis and asthma. Mild allergic conditions may be treated with antihistamines. Antihistamines are not effective in severe allergic reactions e.g. anaphylaxis, as mediators other than histamine are also involved. On the lung the hypersensitivity reaction of histamine is a H1-receptor-mediated bronchoconstriction. On the nasal mucous membranes/skin, the hypersensitivity reaction is a H1-receptor-mediated dilation of terminal arterioles, which leads to the accumulation of red blood cells and produces the redness associated with allergy. In the severe hypersensitivity reaction anaphylaxis, histamine H1-receptor mediated dilation causes a major decrease in blood pressure (hypotension). The H1-receptor-mediated contraction of the endothelial cells of capillaries increases the space between the cells, allowing the contents of the capillaries (fluids, proteins) to flow into extracellular space to cause oedema (hives) (Figure 10.1). Figure 10.1 Oedema with histamine (Copyright QUT, Sheila Doggrell) The other major effect of histamine in the periphery is a H2-receptor mediated increase in gastric secretion. Histamine is released, possibly from the enterochromaffin cells in the gut, and acts at H2-receptors on the parietal cells. Stimulation of the H2-receptors leads to activation of adenylate cyclase, which in turn activated the H+ /K+ ATP-ase, the proton pump. The proton pump, pumps H+ into the stomach to cause the acid environment. 10.1.3 Drugs that modify the actions of histamine Theoretically, the effects of histamine (and any other chemical mediator) can be modified at every level of the system; i.e. at the level of synthesis, release, receptors, cell signaling and breakdown. With histamine we have important drugs that modify at the level of release and receptors. The release of histamine and leukotrienes from mast cells is inhibited by cromoglycate, which is occasionally used in the maintenance treatment of asthma. Cromoglycate is only effective if the histamine and leukotrienes are still in the mast cells. After the histamine and/or leukotrienes have been released, it is too late for cromoglycate to have an effect. Another level at which the effects of histamine is at the receptors. Antagonists at H1- receptors are commonly used in the treatment of allergic rhinitis, conjunctivitis (allergy of the eye), and chronic urticaria (skin allergy). The first generation (older) H1-receptor antagonists crossed the blood brain barrier and caused sedation. Examples of first generation H1-receptor antagonists include dexchlorpheniramine and diphenyhydramine. Dexchlorpheniramine is still used in the treatment of allergic rhinitis, and chronic urticaria, whereas diphenyhydramine is no longer used for hypersensitivity reactions, but is used as a mild sedative in insomnia. The second generation H1-receptor antagonists are less able to cross the blood brain barrier and cause less sedation. An example of a second generation H1- receptor antagonists is fexofenadine. Fexofenadine is used in the treatment of allergic rhinitis and chronic urticarial. Antagonists at H2-receptors revolutionized the treatment of peptic acidity conditions such as peptic ulcer disease, gastro-oesphogus reflux disease (GORD), and dyspepsia, as there had been no good treatments previously. An example of an H2-receptor antagonist is ranitidine (Ranitic). Ranitidine is a relatively safe drug and is available over-the-counter (OTC) without a prescription in low doses. As histamine acting at the H2-receptor is only one of the stimulants of acid secretion, H2- receptor antagonists are only effective against the histamine component. There are other stimulants of gastric secretion such as gastrin and acetylcholine, and H2-receptor antagonists do not inhibit this stimulation of acid secretion whereas proton pump inhibitors do. Thus proton pump inhibitors are often preferred to the H2-receptor antagonists in peptic acidity conditions, as they are more effective. 10.1.4 Cytokines In addition to allergy, cytokines have a role in inflammatory conditions, especially in autoimmune-inflammatory conditions such as rheumatoid arthritis. Cytokines are small secreted proteins that mediate and regulate inflammation, immunity, and haematopoiesis. Cytokines generally act over short distances, short time spans, and at very low concentrations. They act to alter gene expression. Interleukins (IL) are cytokines made by one leukocyte and acting on other leukocytes. There are many interleukins, but IL-1 is the main one associated with inflammation. IL-1 stimulates T-lymphocytes to produce IL-2, which promotes inflammation, and causes fever. IL-2 stimulates growth and activation of other T cells and NK (natural killer) cells. Tumour necrosis factor (TNF) is the other cytokine that has a prominent role in inflammation. TNF kills tumour cells, and hence the name. TNF stimulates the activities of T cells and eosinophils, which are cells involved in the inflammatory process. The interleukin, IL-1, is the main one associated with inflammation. Anakinra is an IL-1 antagonist used in the severe inflammation associated with rheumatoid arthritis. It is administered subcutaneously. Anakinra commonly causes allergy, and treatment has the possibility of allowing serious infection, as the interleukins also have a major role in immunity. Tumour necrosis factor (TNF) is the other cytokine that has a prominent role in inflammation. Infliximab is an antibody to TNF. Infliximab is administered intravenously, every 8 weeks in the hospital setting. During treatment with infliximab, bacterial infection is infrequent. Infliximab is used in the treatment of rheumatoid arthritis and ankylosing spondylitis (degenerative inflammatory arthritis affecting the spine and sacroiliac joints). 10.2 Eicosanoids Eicosanoids are also known as the arachidonic acid derivatives. There are 3 types of eicosanoids; prostaglandins (PGs), thromboxanes (TXs), and Leukotrienes (LTs). The eicosanoids are local hormones, which means they have effects close to where they are produced. 10.2.1 Cyclooxygenase (COX) and lipooxygenase system Arachidonic acid is acquired either as part of meat or from dietary linoleic acid (Figure 17.1). Normally, there is little free arachidonic acid, as it is readily incorporated into the phospholipids of the cell membrane. Figure 10.2 Cyclooxygenase and lipooxygenase pathways (Copyright QUT, Sheila Doggrell) The release of arachidonic acid from the phospholipids of the cell membranes requires the activation of the enzyme phopholipase A2. Phospholipase A2 is activated by a whole range of physical, chemical, hormonal, neuronal and immunological stimuli. Once released, arachidonic acid is readily metabolised. In the areas where the enzyme cyclooxygenase is present, arachidonic acid is metabolised to prostaglandins and thromboxanes. In the areas where the enzyme lipooxygenase is present, arachidonic acid is metabolised to leukotrienes (Figure 10.2). The eicosanoids produced from the cyclooxygenase pathways are prostaglandins (PGs), including PGI2 (which is also known as prostacyclin), and thromboxane A2 (TXA2). The eicosanoids produced from the lipooxygenase pathways are known as leukotrienes (LTs). The effects of all the eicosanoids are local and receptor mediated. The actions of the eicosanoids are short, as they are rapid metabolised (inactivated) and there are no prolonged effects due to recirculation. PGD2 acts at DP receptors, PGE2 acts at EP receptors (which have been further divided into EP1 and EP2), PGF2α acts at FP receptors, PGI2 acts at IP receptors, and TXA2 acts at TP receptors. The products of the lipooxygenase pathway, the LTs, act at LT receptors. 10.2.2 Actions of eicosanoids The eicosanoids have many, many actions. The actions discussed here are those that we modify with medicines. Eicosanoids from both the cyclooxygenase and lipooxygenase pathways have a major role in inflammation. With a variety of physical, chemical, bacterial, and immunological stimuli, phospholipase A2 is activated, and the cyclooxygenase pathway is activated to produced prostaglandins, and the lipooxygenase pathway to produced leukotrienes, and this combination leads to inflammation (Figure 10.3). Figure 10.3 Eicosanoids and inflammation (Copyright QUT, Sheila Doggrell) There are 3 components to inflammation; pain, erythema (redness) and oedema (swelling). The pain is partly due to prostaglandins E2 and I2 which sensitive afferent nerve endings (the sensory nervous system), and this causes an amplification of pain. The erythema is due to both leukotrienes and prostaglandins, with the redness being due to vasodilation and congestion of blood vessels, with localised high concentrations of red blood cells. The oedema is due to the leukotrienes increasing vascular permeability, and causing proteins to leave blood vessels in much the same way as histamine causes oedema (Figure 16.1). To overcome eicosanoids-induced inflammation, drugs must inhibit both the cyclooxygenase and lipooxygenase pathways. The other actions of eicosanoids discussed here are those of the cyclooxygenase pathway only. Firstly, PGE2 has a major role in fever. Fever is associated with disease states, infections, tissue damage, and malignancy. Fever involves increased PGE2 synthesis in hypothalamus, and PGE2 increases set point of body temperature to give the fever. In some situations this can be useful, e.g. increased body temperature probably helps fight bacterial infections by killing the bacteria. However, excessive increases in temperature are harmful to a body designed to act at 370C. To reduce fever, drugs need only inhibit the cyclooxygenase pathway. Secondly, the products of the cyclooxygenase pathway have important roles on the cardiovascular system. PGs cause vasodilation of most vascular beds. An important role for PGE2 and PGI2 is to keep a specialised blood vessel, the ductus arteriosus (lung bypass), open prior to birth. Often the effects of PGI2 and TXA2 oppose each other, thus whereas PGI2 causes vasodilation, TXA2 causes vasoconstriction of most vascular beds. Platelets are a form of blood cells produced in the bone marrow. Platelet aggregation is the first step in coagulation, and PGI2 prevents platelet aggregation, whereas TXA2 increases platelet aggregation. The PGI2 is produced by the activity of the COX in the endothelial cells that line the inside of the blood vessels. PGI2 activates the IP receptors on the platelet cells to increase the activity of adenylate cyclase and levels of cAMP, which prevents platelet aggregation (Figure 10.4). Figure 10.4 Prostacyclin and platelet aggregation (Copyright QUT, Sheila Dog

Is this the question you were looking for? If so, place your order here to get started!