Pathophysiology - Research Paper Example

The Essay Should Say What the Is Anaphylaxis is a dramatic and frightening disease condition that is considered to be a manifestation of severe systemic allergic condition. The know-how of the treatment techniques and ability to deliver a speedy treatment for this condition is crucial in its outcome, in one end of the spectrum recovery, the other end death (Sheikh, A. and Walker, S., 2005). An allergic reaction is a form of body's immune reaction, where the body reacts to several external agents. Anaphylaxis is one of the several type 1 hypersensitivity reaction where the body is hypersenitized and develops IgE or immunoglobulin E, a certain type of protein generated in the body (antibody) in response to certain types of external proteins (antigen). When a person is hypersensitized, these antigens are called allergens. There are certain types of cells in the body called mast cells and basophils in the blood. These cells are excessively activated by the IgE. The fixation of IgE to mast cells is known as sensitization. Sensitization prepares these cells for subsequent antigen-specific activation (Fisher, M. McD., Baldo, B.A., 1993). Hypersensitivity results into a systemic inflammatory response leading to a spectrum of problems ranging from just runny nose to anaphylactic shock to death. This life-threatening aberration of normal immune process, that is, anaphylactic response of a sensitized human appears within minutes after administration or exposure to the specific antigen and is manifested by respiratory distress, often followed by vascular collapse or shock without antecedent respiratory difficulty. Cutaneous manifestations exemplified by pruritus or urticaria with or without angioedema are characteristic. Along with that, there may be gastrointestinal manifestations like nausea, crampy abdominal pain, vomiting, or diarrhoea. The materials that are able to incite an event like this may be many, among them the drugs like penicillin, insulin, antisera, local anesthetics, and other environmental agents are listed (Ewan, P.W., 1996). We will look into the pathophysiology in detail, but for better understanding of the subject, we should learn in nutshell what happens. The normal immune response Adopted from users.rcn.com/.../BiologyPages/A/Allergies.html, Allergies or normal humoral response against a foreign body is that plasma cells secrete IgE. The normal target for IgE is as shown in the figure on the surface of the mast cells and basophils, both involved in the inflammatory response. At the first secretion, this binds to the surface of the mast cells or basophils at specific receptor sites called Fc receptors, and such an IgE coated cell is said to be sensitized to the allergen concerned. A later exposure by the same allergen will reactivate the IgE. The mast cells or basophils have granules laden in it containing a very potent inflammatory agent, histamine. This activated IgE then processes signals for degranulation of mast cells and basophils by GPCRs or chemokine receptors (Austen, K.F., Metcalfe D.D., 1995). These granules then release histamine and other inflammatory substances like cytokines, interleukins, leukotrienes, and prostaglandins into the neighbouring and adjacent tissues causing several systemic effects, such as, dilatation of the vessels, mucous secretion, nerve stimulation, and smooth muscle contraction. We will examine all these issues in relation to the clinical findings of an anaphylactic process, but before that, let us see how things happen (Montanaro, A. and Bardana, E.J. Jr., 2002). Figure 2: Showing the Anaphylactic Process at Cellular level Adopted from British Medical Journal, Pamela W. Ewan, ABC of Allergies: Anaphylaxis, BMJ, 1998; 316, 1442-1445. Apart from this acute phase response of type 1 hypersensitivity reaction, pathologically, there is also a late phase response that happens after the acute phase reactants subside. This happens due to the fact that the original inflammatory response attracts other leukocytes, namely, neutrophils, lymphocytes, eosinophils, and macrophages to the original site. This usually happens starting 4 to 6 hours after and persisting for 1 to 2 days. Mast cell cytokines also are believed to play a role in this process. The question of how the allergen is recognized and presented to the body has attracted investigations, and it has been found that whenever an antigen approaches the body, the antigen is internalized by the antigen presenting cell or APC. The internalized antigen is then processed within the APC. The APC presents this processed antigen to CD4+ T lymphocytes via the MHC or major histocompatibility complex II. After the Antigen or foreign peptide is presented, the T cells differentiate into TH2 T lymphocytes and produces cytokines or lymphokines. These on the other hand cause B cell immunoglobulin isotypes to switch to IgE. Circulating IgE binds to IgE receptors on mast cells. As we have seen already, the original antigen cross links the mast cells with surface bound IgE and results in cellular degranulation to initiate anaphylaxis. Figure 3: Adopted from AnaesthesiaUK, Article on Anaphylaxis . (Gordon J. R. et al., 1990) The patients with anaphylaxis usually present with the features of erythema, generalized pruritus and urticaria, angio-oedema, laryngeal oedema, asthma, rhinitis, conjunctivitis, palatal itching, nausea, vomitimg, abdominal pain, palpitations, sense of impending doom, fainting and lightheadedness, collapse and loss of consciousness. All these can be explained pathophysiologically by the effects of the mediator cytokines, for example, capillary leakage will lead to urticaria, angio-oedema, laryngeal edema, and as a result, asphyxia. Excessive capillary leakage from the vascular pool will lead to hypotension and shock resulting in haemodynamic instability. Mucosal edema may take the form of laryngeal edema, rhinitis, or asthma risking the patient to have asphyxia and respiratory arrest, and smooth muscle contraction may aggravate the bronchial asthma and cause abdominal pain. Individuals differ in the time of appearance of symptoms and signs, but the hallmark of the anaphylactic reaction is the onset of at least some of the manifestations within seconds to minutes after introduction of the antigen, generally by injection or less commonly by ingestion. The airway obstruction may take either of the two forms, upper airway and lower airway. Laryngeal oedema may be experienced as a lump in the throat, hoarseness, or stridor. The bronchial obstruction will be felt as tightness in the chest and/or audible wheezing. A characteristic feature is eruption of well-circumscribed discrete cutaneous wheals with eythematous, raised, serpiginous borders and blanched centers. These urticarial eruptions are immensely pruritic since they are induced by histamine and are usually disseminated but may be localized. These seldom persist beyond 48 hours, and they may coalesce to form giant hives. A localized nonpitting oedema or angio-oedema may persist. (Austen K.F. and Metcalfe D.D, 1995). Looking into the pathophysiology of the more serious findings, the pathology in the lungs compromising breathing is mainly due to peribronchial congestion, submucosal edema, and eosinophilic infiltration. The angio-oedema and urticarial manifestations of the anaphylactic syndrome have been attributed to release of endogenous histamine. A role of released cysteinyl leukotrienes in causing fatal bronchiolar constriction by inducing massive smooth muscle constriction has been suggested. The process of vasodilatation has been attempted to be explained in relation to profuse histamine release and intravascular coagulation and release of kinins. It is suspected that PGD2 prostaglandins play important roles in hypotensive anaphylactic reactions (Berger, A., 1999). The key to the management of anaphylactic shock is awareness of the physician, ability to recognize anaphylaxis early, expertise to treat quickly, and that makes anaphylaxis easily treatable. The outcome of an early treatment is gratifying since most of the cases also respond positively and rapidly to appropriate treatment. Most deaths happen, if not intervened, within minutes to hours of the first symptoms. The cornerstones of treatment are steroids, bronchodilators, and antihistamines. We will study the effects of these drugs while discussing the pharamacology of these drugs both in terms of pharmacokinetics and pharmacodymanics. Steroids: Adrenaline is the most important drug for the management of anaphylaxis after the mandatory early recognition of anaphylaxis. It should be given as soon as possible. In a clinical review McLean-Tooke and his collaborators (2003) suggest that adrenaline should be given intramuscularly initially, but mild pruritus and urticaria could be controlled by 0.2 to 0.5 mL of 1:1000 epinephrine subcutaneously, while the intravenous route should be reserved for more severe cases. Giving it subcutaneously or inhaled may not be as effective as giving it intramuscularly (British National Formulary, 2007). The recommended dose varies between 0.3 to 1.0 mg for adults and for most patients one timely dose is enough. The patients who are judged to be having life- threatening allergies in a recurrent manner should carry adrenaline autoinjectors but only a few patients are confident in using them, how and when (McLean-Tooke et al., 2003). The physiological benefits of adrenaline are achieved from the fact that the pharmacologic action of this agent resembles the effects of stimulation of the adrenergic nerves. To a variable degree, it acts on both alpha and beta receptor sites of sympathetic effector cells. Stimulation of the alpha adrenoceptors increases peripheral vascular resistance, thus improving blood pressure and coronary perfusion. Reversal of peripheral vasodilatation, thus, causes decrease of the angio-oedema. Given by rapid intravenous injection, it produces rapid rise of blood pressure via direct cardiotonic action on the cardiac muscles and increases the strength of systolic ventricular contraction, increases the heart rate by chronotropic action, and causes increases in peripheral resistance by causing constriction in the blood vessels of the skin, mucosa, and visceral circulation. These actions are mediated mainly respectively by beta 1 and beta 2 receptors. It is clearly demonstrable that this drug antagonizes the pathophysiology of the anaphylactic process. Other than this, adrenaline relaxes the smooth muscles of bronchi by stimulation of beta 2 receptors and increases intracellular cyclic adenosine monophosphate production in mast cells and basophils reducing release of inflammatory substances and is a physiologic antagonist of histamine (The British National Formulary, 2007). Histamine and related cytokines are the primary causes of an anaphylactic reaction in the biochemical level, and it is not difficult to presume in the setting of a severe anaphylactic reaction attended with respiratory difficulty and/or hypotension, (Brown, A.F.T., 1998) adrenaline is the drug of choice for first line treatment and rapid reversal of the condition. This is a clinical finding that onset of anaphylaxis can be threatening, and rapid diagnosis and speedy treatment with adrenaline can be more rewarding almost going to the extent of miraculous recovery (Stewart A.G. & Ewan P.W., 1996). Intravenous injection produces an intensified and immediate response. Following intravenous injection, adrenaline rapidly disappears from the blood stream. This drug is rapidly inactivated in the body and is degraded by enzymes in the liver and other tissues. The larger portion of the injected dose is excreted in the urine as inactivated compound, and the remainder is excreted either partly unchanged or conjugated with bilirubin. This drug is steroid in nature, hence easily binds to the tissues at specific receptor cites. This is inactivated chiefly by enzymatic transformation to metanephrine or normetanephrine, either of which is subsequently excreted in the urine being water soluble in the form of sulphates or glucuronides. Either of the chemical reaction sequences results in the formation of 3-methoxy-4-hydroxy-mandelic acid or VMA or vanillyl mandelic acid. This product is also detected in urine (Brunton, L.L., Parker, K.L. and Lazo, J.S., 2005, p. 2001). Antihistamines: This adrenaline should be followed by diphenhydramine or chlorpheniramine, an antihistaminic, intramuscularly or intravenously. This is usually all that is required provided the treatment is started early. Treatment failure happens most commonly if adrenaline is delayed. If respiratory difficulty or hypotension is absent, it is better to take recourse to antihistaminic and then reassess. Chlorpheniramine is a propylamine antihistaminic agent, chlorpheniramine maleate occurs as an odourless, white, crystalline powder. These are chemically H1 receptor antagonists. They competitively inhibit histamine at H1 receptor sites. They do not inactivate or prevent the release of histamine, that is, they can block the H1 receptor sites so that the released histamine cannot interact with the cell, this preventing histamine's action on the cell. Besides their antihistaminic activity, these agents have varying degrees of anticholinergic and CNS activities. Some other agents of the same class of drugs have antiemetic activity or antiserotonin activity. These drugs are used in anaphylaxis to counteract histamine mediated symptoms. This drug is well absorbed after oral administration, but because of relatively high degree of metabolism in the GI mucosa and in the liver, only about 25% to 60% drug is available for use, whereas this is well distributed after an intravenous injection with a steady state volume distribution of 2.5 to 3.2 L/kg, and it is about 70% bound to plasma proteins. It is unknown if chlorpheniramine is excreted in the milk. It is metabolized in the liver, and practically all the drug, metabolized and unchanged, is excreted in the urine. In patients with normal renal and hepatic functions, the terminal serum half-life ranges from 13.2 to 43 hours (The British National Formulary, 2007). In some cases, bronchodilators along with oxygen is used to aid respiratory distress in anaphylactic reaction. The drug recommended is theophylline or amniphylline, 0.25 to 0.5 mg intravenously with the running intravenous line. This proves helpful for urticaria-angio-oedema and bronchospasm. Pharmacologically, this is a xanthine derivative, and its primary action is that of bronchodilatation, but it also exhibits peripheral vasodilatory and other smooth muscle relaxing activity to a lesser degree. The bronchodilatory action of these xanthine derivatives are believed to be mediated through competitive inhibition of phosphodiesterase with a resultant increase in cyclic AMP that relaxes the bronchial smooth muscles. These are rapidly absorbed in the active form, and a therapeutic mean peak plasma concentration is reached in a span of 45 minutes following a single dose. The bronchodilatation is produced directly, and the excretion happens through kidneys as a mixture of changed and unchanged forms. The plasma levels are dose related, and in two hours 80% of the dose is excreted unchanged through the urine, hence in patients with impaired renal function, the dose needs to be adjusted (The British National Formulary, 2007). This completes the brief discussion of pharmacodynamics and pharmacokinetics of the drugs that are used for management of an anaphylactic reaction. Now we shall look into the traditional Chinese Medicine and its approach to acute allergic reaction that might lead to asthma. In Chinese Medicine theory, the acute allergic response is differentiated between the actual attacks and the period between attacks. In an acute attack, this is considered to be an excess condition in which Wind, a nonsubstantial pathogenic factor lodges in the bronchi and combines with Cold and Heat pathogenic factors to cause the bronchospasm of acute allergic reactions. Acupuncture is remarkable in stopping these acute attacks. Apart from that, herbal Chinese medicines have shown very encouraging effects in counteracting the effects of acute allergic phenomenon. Research on the efficacy of acupuncture and herbal medicine in treatment of acute allergic response manifested by asthma shows that Chinese medicine compares favorably with standard Western treatment and provides an alternative for those who would avoid long-term use of drugs and strengthen their natural defenses (Liu ,W. & Gong, C., 2006). Reference List Anaesthesia UK, (2006). Management of Latex Allergy, Immunological Mechanism of Anaphylaxis, Retrieved on April 23, 2007 from http://www.anaesthesiauk.com/article.aspxarticleid=100086. Andrew. P. C., McLean-Tooke, Claire, A.B., Fay, C.A., and Spickett, G. (2003). Adrenaline In The Treatment Of Anaphylaxis: What Is The Evidence British Medical Journal, 327: pp. 1332-1335. Austen, K.F. and Metcalfe, D.D.(1995). Anaphylactic Syndrome, Immunological Diseases, 5th Ed, M. Frank et al. (Eds.) Boston Little Brown. Berger, A. (1999). Science Commentary: What Are Leukotrienes And How Do They Work In Asthma British Medical Journal, 319: p. 90. Brown, A.F.T. (1998). Therapeutic Controversies in the Management Of Acute Anaphylaxis. Journal of Accidental Emergency Medicine;15: pp. 89-95. Brunton, L., Parker, K., and Lazo, J. (2005), Goodman and Gillman's The Pharmacological Basis of Therapeutics, Immunology, McGraw Hill Publishing, 2001-2006. Ewan, W. P. (1998). ABC of Allergies: Anaphylaxis, British Medical Journal, 316, pp.1442-1445. Ewan, W. P. (1998). ABC of Allergies: Anaphylaxis, British Medical Journal; 316, pp. 1442-1445. Ewan, W. P.(1998). ABC of Allergies: Anaphylaxis, British Medical Journal; 316, pp. 1442-1445. Fisher, M.M. and Baldo, B.A., (1993). Anaphylactic Reactions During Surgical And Medical Procedures. Journal of Allergy and Clinical Immunology,Volume 110,Issue 2,Pages S64-S69 P. Lieberman. Gordon J. R. et al. (1990). Mast Cells as a Source of Multifunctional Cytokines, Immunology Today, 11:p. 458. Kimball, J.W. (2006), Mast Cell, Biology Pages, Retrieved on April 23, 2007 from http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/M/MastCell.gif Liu ,W. and Gong, C.(2006), The American Academy of Acupuncture and Oriental Medicine, Expert Advice-Treatment of Asthma in Traditional Chinese Medicine(TCM):Traditional Chinese Medicine information page, Retrieved on April 23, 2007, from http://www.tcmpage.com/hpasthma.html Reference List Montanaro, A. and Bardana, E.J., Jr., (2002). The Mechanisms, Causes And Treatment of Anaphylaxis, Journal of Investigative Clinical Immunology,;2: pp.2-11. Sheikh, A. and Walker, S. (2005). Anaphylaxis, British Medical Journal, 331: p.330 doi:10.1136/bmj.331.7512.330. Stewart, A.G.and Ewan, P.W. (1996). The Incidence, Aetiology, and Management of Anaphylaxis Presenting to an Accident and Emergency Department. The Quarterly Journal Of Medicine;89:pp. 859864. The British National Formulary: adrenaline, aminophylline, and diphenhydramine. 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