Drug+Reactions+(Anaphylactoid,+Anaphylaxis,+Idiosyncratic)

toc 1) =** Anaphylaxis **= severe, whole-body hypersensitivity reaction to a chemical that has become an allergen. Type 1 hypersensitivity reaction that is almost immediate.
 * 1) == Three main //classifications// ==
 * 2) __ Anaphylactic shock __ is associated with systemic [|vasodilation] that causes [|low blood pressure] which is by definition 30% lower than the person's baseline or below standard values
 * 3) __ Biphasic anaphylaxis __ is the recurrence of symptoms within 1–72 hours with no further exposure to the allergen
 * 4) __ Anaphylactoid __ (see below)
 * 5) == Pathophysiology//(1)// ==
 * 6) Allergen introduced: susceptible person forms specific IgE antibodies
 * 7) 2nd exposure leads to IgE antibodies binding to basophils and mast cells.
 * 8) widespread mast cell degranulation leading to **histamine** release
 * 9) Increases vascular permeability
 * 10) Widespread constriction of smooth muscle
 * 11) Vasodilation
 * 12) Mucus secretion
 * 13) Reaction is amplified by PAF (platelet activation factor) which causes platelet aggregation and release of histamine, heparin and vasoactive amines.

2)
 * 1) == Symptoms ==
 * 2) Skin: hives, itching, swelling, blue tinge (due to hypoxia)
 * 3) Respiratory: bronchoconstriction
 * 4) Could lead to stridor, wheezing, shortness of breath
 * 5) Hoarseness, pain with swallowing, and cough
 * 6) Cardiovascular
 * 7) Coronary artery spasm: MI, Cardiac arrest, dysrhythmia
 * 8) Increased heart rate with hypotension
 * 9) Lightheadedness, shock
 * 10) GI: crampy abdominal pain, diarrhea, vomiting
 * 11) GU: loss of bladder control, cramps
 * 12) Neuro: altered mental status, sense of “impending doom”
 * 13) == Treatment ==
 * 14) ** Epinephrine ** : Primary treatment with no absolute contraindications
 * 15) Recommended to be given IM (0.3-0.5mg, 1:1000 concentration)
 * 16) Can be repeated every 5-15 minutes. ~36% need 2nd dose
 * 17) IV dose (4mcg or 0.5mL of a 8mcg/mL syringe)
 * 18) People on beta blockers may be resistant to effects
 * 19) Can give glucagon to counteract blockade
 * 20) Support airway, IV fluids, discontinue offending agent

** Anaphylactoid ** :
type of anaphylaxis that does not involve an allergic reaction or immune response, but is due to direct mast cell [|degranulation] 3) =** Idiosyncratic: **= Adverse reactions that occur in a small amount of patients. Most reactions occur with medications that form active metabolites.  // (4) //
 * 1) Patient never exposed to substance previously
 * 2) No antibodies to agent
 * 3) Agent directly caused histamine release from mast cells
 * 4) Signs and symptoms directly mirror anaphylactic reaction
 * 5) Could potentially lead to life-threatening situation
 * 6) Other than history of exposure, the conditions are indistinguishable and are treated exactly the same.
 * 1) Hapten Hypothesis
 * 2) Small molecules or active metabolite irreversibly bind proteins, becoming haptens, that lead to an immune response
 * 3) Good example is halothane
 * 4) Halothane is oxidized by cytochrome P450 to the reactive trifluoroacetyl chloride
 * 5) Halothane induced hepatotoxicity due to antibodies formed against hapten of the reactive metabolite
 * 6) These patients also have antibodies against native proteins such as protein disulfide isomerase. Protein disulfide isomerase is also a target for the reactive metabolite of halothane
 * 7) Implies that modification of a protein by reactive metabolite has led to immune response//(2)//
 * 8) Danger Hypothesis
 * 9) The nonself nature of a foreign antigen is not what induces an immune response; instead, it is “danger signals,” such as cell damage or infection, that activate the immune system.
 * 10) Requires 2 signals
 * 11) // Signal 1 //, which is the T-cell-receptor-mediated recognition of an MHC-restricted antigen
 * 12) // Signal 2 //, which represents the interactions between various costimulatory ligands and receptors between the T cell and the APC, such as CD28:CD86 and CD40:CD154//(3)//
 * 13) Without this signal, signal 1 simply leads to tolerance either by anergy or by apoptosis of responding T cells
 * 14) Several studies have focused on the ability of stressed, dead, or dying cells to provide maturation signals to dendritic cells.
 * 1) Pharmaceutical Interaction (P-I) Hypothesis//(5)//
 * 2) Hypersensitive response where T cells respond so quickly, that they would not be able to process antigen or hapten.
 * 3) Bypass antigen presenting process
 * 4) Pharmacologically binding MHC II complexor drug specific T-cell receptors
 * 5) Acts reversibly on the receptors of the immune cells
 * 6) Only happens in cells already sensitized to drug

=** References **= 1) Parham, Peter. __The Immune System__. 2nd Edition. New York, NY. Garland Science 2005 2) Uetrecht, J. (2007) Idiosyncratic drug reactions: Current understanding.//Annual Re////view. Pharmacol. Toxicol. 47//, 513–539. 3) Sanderson JP, Naisbitt DJ, Park BK. Role of Bioactivation in Drug-Induced Hypersensitivity Reactions. //AAPS Journal//. 2006; 8(1): E55-E64  4) Uetrecht, J. (2008) Idiosyncratic drug reactions: Past, Present, Future. // Chem. Res. Toxicology //**, **// 21, // 84–92 5) Coleman, Michael. __Human Drug Metabolism__. 2nd Edition. West Sussex, UK. Wiley Blackwell 2010.

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