Term
| what is a type I hypersensitivity reaction? |
|
Definition
| a rapid immunologic reaction occuring within minutes after a combination of an antigen (allergen) w/an antibody bound to mast cells in individuals previously sensitized to the antigen |
|
|
Term
| what is the pathophysiology of a type 1 hypersensitivity/allergic reaction? |
|
Definition
| the allergen is presented to helper T cells (TH2), which are then activated and produce IL4. IL4 then promotes class switching in B cells to the IgE isotype - which then becomes the major mediator of the allergic reaction. if this is the pts first exposure to this allergen they are now sensitized. if this is a repeat exposure to the allergen, IgE then binds to the mast cells, causing them to degranulate. |
|
|
Term
| are there phases to an allergic reaction? |
|
Definition
| yes, an immediate and later phase (occurs 2-24 hrs later). this is b/c the immediate release of mast cell mediators consists of whatever the cell already stored and the late phase consists of mediators produced via de novo synthesis |
|
|
Term
| what parts of the body are affected by mast cell mediators? |
|
Definition
| the GI tract (increased peristalsis/fluid secretion), airways (decreased diameter/increased mucus secretion), and blood vessels (increased blood flow and permeability -> edema) |
|
|
Term
| what is one of the immediate mast cell mediators that plays a major role in allergic reactions? |
|
Definition
|
|
Term
| what are some other immediate mast cell allergic mediators other than histamine? |
|
Definition
| proteases and chemotactic factors, arachidonic acid (from which you get prostaglandins and leukotrienes) and platelet activating factor. |
|
|
Term
| what is the cumulative effect of the immediate mast cell degranulation? |
|
Definition
| vasodilation, vascular leakage, and smooth muscle spasm |
|
|
Term
| what is the late phase mast cell mediated allergic reaction characterized by? |
|
Definition
| infiltration of WBCs, (specifically TH2 cells and eosinophils), epithelial damage and bronchospasm |
|
|
Term
| what is the major effect of histamine? |
|
Definition
| vascular leakage, leading to runny nose, watery eyes and tissue edema. bronchospasm is also an effect of histamine. |
|
|
Term
| what is a major effect of the lipid mediators (TNF, enzymes, platelet activating factor, prostaglandins, leukotrienes, and cationic granule proteins) released by mast cells? |
|
Definition
|
|
Term
| what are all of the first wave mediators? |
|
Definition
| histamine, heparine, chondroitin sulfate, enzymes and TNF-alpha |
|
|
Term
| what receptors does histamine work on? |
|
Definition
| 3 receptors, H1-3, H1 being the most important in allergic rxns. |
|
|
Term
| what is the effect of histamine release on the body? |
|
Definition
| smooth muscle constriction, increased blood vessel endothelium permeability/extravasation of fluid, and increased mucus production |
|
|
Term
| what other than histamine is release as first wave mediators? |
|
Definition
| heparin (anti-coagulant), chondroitin sulfate (proteoglycan), enzymes (neutral proteases, acid hydrolases), and TNF-alpha (acts in concert w/histamine to activate endothelial cells/increase expression of adhesion molecules - proinflammatory) |
|
|
Term
| why is TNF-alpha not targeted in pharmacology? |
|
Definition
| b/c it is a non-major mediator |
|
|
Term
| what composes the second wave of mast cell mediators |
|
Definition
| these mediators are synthesized de novo and include: cytokines IL-4, TNF-alpha (seen in both early and late phase rxn), prostaglandins, and the leukotrienes |
|
|
Term
| what is the most abundant mediator produced in mast cells via the COX pathway? what effect does it have? |
|
Definition
| prostaglandin D2 - which promotes vascular dilation/increased permeability and intense bronchospasm. it also functions as a chemoattractant for neutrophils |
|
|
Term
| what are some of the most potent and spasmogenics agents known, that also happen to be released in the late phase allergic rxn from mast cells? |
|
Definition
| leukotrienes C4 and D4 have activities similar to antihistamine, but are 100-1000x more potent in inducing inflammation, smooth muscle contraction, airway constriction (smooth muscle contraction), and mucus secretion -> which is why they are targeted for pharmacologic tx of asthma |
|
|
Term
| what does leukotriene B4 do? |
|
Definition
| leukotriene B4 is highly chemotactic for neutrophils, eosinophils(important component of late phase inflammatory rxn), and monocytes |
|
|
Term
| what is the most serious possible type 1 hypersensitivity rxn? |
|
Definition
| systemic anaphylaxis - consisting of edema, increased vascular permeability, tracheal occlusion, circulatory collapse and death. epinephrine needs to be administered immediately |
|
|
Term
| what are other clinical manifestations of a type 1 hypersensitivity rxn (other than anaphylaxis)? |
|
Definition
| wheal/flare (localized allergic rxn), allegic rhinitis (usually from inhaled allergens), and bronchial asthma (pollen, dust, and food allergies) |
|
|
Term
| what drugs have been the mainstay of anti-allergic/type 1 hypersensitivity rxn treatment for many years? |
|
Definition
| anti-histamines, which mainly act on the H1 receptor which mediates its effects on smooth muscle (vasodilation, increased vascular permeability, and contraction of non-vascular smooth muscle) |
|
|
Term
| what is the common M/A for the H1 receptor antagonists? |
|
Definition
| competitive antagonism of the H1 receptor (which is a G protein coupled receptor) |
|
|
Term
| what is the common chemical structure between H1 receptor antagonists? |
|
Definition
| 2 joined 6C ring structures |
|
|
Term
| what are the indications for H1 receptor antagonists? |
|
Definition
| allergic rhinitis (rhinorrhea, sneezing, itching of the eyes, and nasal mucosa), the common cold (dries out the nasal mucosa, but virally mediated colds benefit more from nasal decongestants/analgesics), and allergic dermatitis |
|
|
Term
| what are other indications of 1st gen H1 receptor antagonists? |
|
Definition
| sedation (pre-anesthetic, anti-nausea, anti-emetic, inhibition of salivary/bronchial secretions) and anti-parkinsons (reduction of muscle rigidity and tremors) |
|
|
Term
| why are H1 receptor antagonists not particularly useful in asthma? |
|
Definition
| histamine does not appear to be the major mediator in an asthmatic response. asthma has more of a chronic pathophysiology related to leukotrienes, which is why anti-inflammatory drugs such as corticosteroids are often useful. |
|
|
Term
| what are some drug interactions associated with the H1 receptor antagonists? |
|
Definition
| anti-histamines produce sedation that can potentiate CNS depressants (barbiturates, opiates, anesthetics, alcohol). anti-histamines also have anti-cholinergic effects that can produce excessive effects if administered with other anti-cholinergics |
|
|
Term
| what are the 1st gen H1 receptor antagonists? |
|
Definition
| alkylamines, ethanolamines (dimenhydrinate and *diphenhydramine), piperazine and phenothiazine |
|
|
Term
| what are the 2nd gen H1 receptor antagonists? what differentiates these from the 1st gen? |
|
Definition
| piperidine-fexofenadine, loratidine, and cetirizine. these have the same M/A and act on the H1 receptor - but are nonsedative |
|
|
Term
| what are the major side effects of the 1st gen anti-histamines? advantages? routes of adm? |
|
Definition
| side effects: sedation and anti-cholinergic. advantages: inexpensive, OTC. routes of adm: oral/topical/injection |
|
|
Term
| what are the pros/cons of the 2nd gen anti-histamines? what are they mainly used for? |
|
Definition
| these are non sedating, however they are more expensive than the first generation. they are mainly used for allergic rhinitis and chronic urticaria |
|
|
Term
| what is the model drug of the 1 gen H1 antagonists? what can it be used for? what are side effects related to its anticholinergic action? |
|
Definition
| diphenhydramine - which can be used for its sedative effects, anti-motion sickness effects, anti-parkinsons (dystonia) activity, and tx of extra-pyramidal symptoms associated with anti-psychotics. diphenhydramine can also cause urinary retention and blurred vision as a result of its anticholinergic action on peripheral muscarinic receptors. |
|
|
Term
| what toxicities are associated with the 1st gen H1 antagonists? |
|
Definition
| major: sedation and anti-muscarinic action. less common: excitation and convulsions in children, postural hypotension, and allergic rxns (very rare). |
|
|
Term
| what does an OD of the H1 antagonists resemble? |
|
Definition
| atropine OD: dry as a bone, blind as a bat, red as a beet, mad as a hatter. (dryness of mouth, hallucinations, delirium, a lot of redness of face, mydriasis) |
|
|
Term
| what are the potential drug interactions for the 1st gen H1 antagonists? |
|
Definition
| any drug that causes CNS depression (alcohol/sedatives/tranquilizers) and the autonomic effects of older drugs that are additive with those of muscarinic and alpha-blocking agents |
|
|
Term
| what is bronchial asthma? what causes it? |
|
Definition
| bronchial asthma: airway inflammation due to bronchial hyperreactivity to allergens, irritant chemical/pollutants, cold/dry air, exercised, ASA/NSADs, and respiratory infection |
|
|
Term
| what are the symptoms of bronchial asthma? |
|
Definition
| chest tightness, bronchoconstriction, secretions, cough, wheeze, and decreased FEV |
|
|
Term
| what does bronchial asthma look like histologically? |
|
Definition
| there is epithelial sloughting, hypertrophy/hyperplasia of airway smooth muscle, increased airway wall thickness, inflammation/edema, mucus gland hypertrophy/hypersecretion of mucus, mucus plugging, and hyperinflation of the lungs |
|
|
Term
| what does activation of the beta2 receptors do to bronchial smooth muscle? |
|
Definition
| activation of the beta 2 receptors relaxes bronchial smooth muscle |
|
|
Term
| how does cholinergic stimulation affect the bronchial smooth muscle? |
|
Definition
| cholinergic stimulation will constrict bronchial smooth muscle (opposite of adrenergics) |
|
|
Term
| what does early/immediate phase response consist of and what mediates it? |
|
Definition
| the early/immediate phase response consists of bronchoconstriction due to mast cell degranulation |
|
|
Term
| who does the late asthmatic phase response occur in? why? |
|
Definition
| ~50% of adults due to an inflammatory process/allergic rxn that keeps going (TH2 lymphocytes, cytokines, eosinophils) |
|
|
Term
| what are the 2 types of drug control for asthma? |
|
Definition
| reliever and controller drugs |
|
|
Term
| what are the asthma reliever (rescue) drugs? |
|
Definition
| bronchodilators which work through the adenylate cylase system and increase cAMP production or have beta 2 agonist action. these are used to relieve an early asthmatic response |
|
|
Term
| what are the asthma controller drugs? |
|
Definition
| these are the antiinflammatory drugs; steroids, mast cell stabilizers, and leukotriene antagonists. these drugs are taken daily for regular control. |
|
|
Term
| what does the asthma reliever drug class consist of? |
|
Definition
| methylxanthines, sympathomimetics, and antihistamines. these have bronchodilator action effects plus effects on mucus production, cilia, and mast cell mediator release |
|
|
Term
| how does manipulation of cAMP by xanthines (theophyline) and beta 2 agonists increase brochodilation? |
|
Definition
| cAMP increases bronchodilation, and beta 2 agonists increase its production while xanthines inhibit its breakdown (by phosphodiesterase) |
|
|
Term
| how does administration of xanthines (theophyline) and muscarinic antagonists decrease brochoconstriction? |
|
Definition
| muscarinic antagonists block ACh and xanthines block adenosine, and the effect of either leads to decreased bronchoconstriction |
|
|
Term
| what is the M/A of methyxanthines in fighting allergic rxns? |
|
Definition
| methylxanthines inhibit phosphodiesterase, which decreases cAMP breakdown which leads to increased bronchodilation. methylxanthines also block the adenosine receptor - inhibiting bronchoconstriction |
|
|
Term
| what are the 2 methylxanthines used in acute allergic rxn prevention? what is the effect of their administration? |
|
Definition
| theophylline and aminophylline: both of which are IV, have a slower onset and less potency than beta 2 agonists. administration of theophylline or aminophylline will increase skeletal muscle contractility, decrease muscle fatigue, and increase mucociliary clearance |
|
|
Term
| what are the ADRs associated with the methylxanthines? |
|
Definition
| GI, CNS stimulation (seizures), cardiac stimulation (arrhythmias) |
|
|
Term
| what is the M/A of sympathomimetics used in tx of acute allergic rxns? |
|
Definition
| the beta 2 receptors in the lungs are not directly stimulated by adrenergic nerve endings - they are stimulated only by circulating drugs/catecholamines. their activation by either leads to increased cAMP production which increases bronchodilation AND inhibits release of bronchoconstrictor mediators from mast cells. (it is also thought that beta 2 agonists inhibit microvascular leakage and increase mucociliary transport by increasing ciliary activity) |
|
|
Term
| what is the best sympathomimetic agent for acute allergic/asthmatic attacks? |
|
Definition
| epinephrine, however it is not recommended for routine use b/c in high doses alpha receptors will be stimulated, resulting in tachycardia, arrhythmia, vasoconstriction, and bronchoconstriction |
|
|
Term
| what is the caution with using isoproterenol as tx for allergic/asthmatic attacks? |
|
Definition
| isoproterenol has beta 2 agonist activity which helps with bronchodilation, but also has beta 1 activity (non-selective) which can lead to arrhythmias via CO stimulation, so it should not be used on a routine basis |
|
|
Term
| what are more common drugs in asthma rescue inhalers? |
|
Definition
| selective beta 2 agonists. older gen (3-4 hrs duration): metaproterenol, pirbuterol, terbutaline, albuterol and levabuterol. newer gen (12 hr duration): salmeterol and formoterol |
|
|
Term
| what are ADRs for terbutaline and albuterol? |
|
Definition
| skeletal muscle tremor, nervousness, weakness, peripheral vasodilation (dose related) |
|
|
Term
| what is the difference between albuterol and levalbuterol? |
|
Definition
| albuterol is a racemic mixture of S&R enantiomers, while levalbuterol is only the R enantiomer. the R enantiomer is 100x more selective for the beta 2 receptor than the S and therefore levalbuterol causes slightly less cardiac stimulation. there is also evidence the s-albuterol may cause paradoxical bronchospasm by increasing Ca in smooth muscle |
|
|
Term
| what differentiates the newer generation of selective beta 2 agonists from the older generation? |
|
Definition
| the newer generation (salmeterol, formoterol) are long lasting (12 hrs) but take longer to have an effect (10-15 min) than the older generation (albuterol - <5 min). therefore the newer generation is better used as prophylaxis as opposed to acute tx and has been associated with a small number of asthma related deaths |
|
|
Term
| what are concerns for chronic beta 2 agonist tx? |
|
Definition
| tolerance may occur leading to tachyphylaxis, decreased peak effect and decreased duration of action. rebound bronchospasm may also occur. both of these effects can lead to worsening of asthma symptoms and an increase in bronchial hyperreactivity |
|
|
Term
| what is the M/A for antimuscarinics? |
|
Definition
| blocking ACh receptors in the airway. (ACh is released from the vagus which results in contraction of smooth muscle and increases mucus secretion) |
|
|
Term
|
Definition
| a muscarinic receptor blocker that reduces sputum volume w/o increasing viscosity and is a modest bronchodilator. it is usually combined with beta 2 agonists (attacking both sides of bronchodilation and constriction) and has a slow onset (not for emergencies). it may cause respiratory dryness, irritation and cough |
|
|
Term
|
Definition
| a long-acting anticholinergic bronchodilator (similar to ipratropium) indicated mainly for COPD, but could have some application in asthma |
|
|
Term
| what is the general M/A for corticosteroids in asthma? |
|
Definition
| inhibition of gene expression responsible for inflammatory protein production via intracellular receptor activation (COX inhibition). thus mast cells are stabilized, PG/leukotriene synth is decreased as well as decrease in WBC/eosinophil/IgE antibody production. corticosteroids are used in acute conditions and ADRs include dysphonia and oropharyngeal candidiasis |
|
|
Term
| what are the corticosteroids we should be able to recognize? |
|
Definition
| beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone, and triamcinolone |
|
|
Term
| what are the mast cell stabilizers? what is their M/A? |
|
Definition
| cromolyn and nedocromil, which reduce the ability of mast cells to release some of their inflammatory mediators, they reduce sensory nerve reflexes (inhibit sensory feedback cycle), and also inhibit the activation of Cl channels which decreases Ca activation |
|
|
Term
| can the mast cell stabilizers (cromolyn/nedocromil) help with allergic rhinitis or stomach reactions? |
|
Definition
|
|
Term
| do the mast cell stabilizers (cromolyn/nedocromil) help with the early and late phase allergic rxn? |
|
Definition
|
|
Term
| what are the ADRs associated with the mast cell stabilizers? |
|
Definition
| local irritation, bronchospasm, cough, wheezing, bad tast, headache/dizziness |
|
|
Term
| what is the primary target of the leukotriene inhibitors? |
|
Definition
| antagonism of the the leukotriene D4 receptor. this covers LTD4, however LTC4 and LTE4 are also implicated in bronchconstriction and LTB4 is a potent neutrophil chemoattractant |
|
|
Term
| which are the leukotriene inhibitors? what is their M/A? effect? |
|
Definition
| zafirlukast and montelukast both antagonize cysLT1 receptor which blocks LTD4 action. zafirlukast and montelukast are thus used to reduce/control chronic inflammation of asthma and allow for reduction of reliever/steroid drug dosages. they are also indicated for ASA-induced asthma |
|
|
Term
| what does the fact that zafirlukast inhibits p450 mean? |
|
Definition
| zaifirlukast will decrease the metabolism of other drugs such as warfarin or phenytoin by inhibition of p450 |
|
|
Term
| what are ADRs associated with zafirlukast? |
|
Definition
| headache/dizziness, increased liver enzyme, myalgia/back pain, infection. there is also churg-strauss syndrome associated with this drug (vasculitis/granuloma formation) |
|
|
Term
| what is unique about montelukast? ADRs? |
|
Definition
| it is a more specific cysLT1 blocker w/no significant drug interactions. ADRs include: headache/dizziness, rash, GI, nasal/ear/throat/resp congestion/infections |
|
|
Term
|
Definition
| an IgE monoclonal antibody that will prevent IgE from binding to mast cells. it has a good efficacy and half life (26 days) and is indicated for mod-severe persistant asthma uncontrolled by steroids. it is expensive and painful injection site rxn is a possible ADR as well as anaphylaxis. M/A: opsonization of IgE for clearance by macrophages |
|
|
