Final Exam (12/9-12/11)

Question 1

Mast Cells and histamine

Answer 1

Tissue injury causes release of chemical signals from mast cells, like histamine. These signals help to vasodilate vessels around the injury allowing for migration of phagocytes to the area.

Question 2

Clinical Symptoms associated with histamine release

Answer 2

Mild/cutaneous symptoms: erythema (redness), urticaria (hives), and/or itching

mild to moderate symptoms: skin reactions, tachycardia, dysrhythmias, moderate hypotension, mild respiratory distress

severe/anaphylactic: severe hypotension, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrest

Question 3

Histamine

Answer 3

biogenic amine synthesized in the Golgi apparatus. Produced from histidine by HDC (histidine decarboxylase).

Question 4

Histamine Metabolism

Answer 4

produces other products that are important in the body

Question 5

Histamine storage

Answer 5

In most tissues, histamine is stored in mast cells. Mast cells and histamine are very abundant in skin, bronchial mucosa and intestinal mucosa.

In blood, histamine is stored in basophils

Question 6

Histamine Functions

Answer 6

inflammation, gastric acid secretion, modulating neurotransmitter release, immune cell differentiation. function depends on subtype.

Question 7

Histamine Subtypes

Answer 7

H1R: allergy and inflammation. Gq receptor with second messengers of calcium, PLC, NO and cGMP. Inverse agonists (H1 antihistamines) bind to and stabilize the receptor in the active state

H2R: gastric acid. Gs with cAMP as the second messenger. Receptor antagonists block binding of histamine to the receptor.

H3R: CNS. Gi/o with second messenger of cAMP or MAP kinases.

H4R: immune cell functions. Gi/o with second messenger cAMP and Ca. Found in hematopoietic origin cells (spleen for example)

Question 8

Allergy Sequence of events

Answer 8

1. Allergens elicit release of histamine from mast cells
2. Histamine receptors are activated
3. Physiological responses are generated: hives/rash, runny nose, itchy eyes and wheezing

Question 9

“Classical Allergic Initiation Pathway”

Answer 9

1. Allergen enters the body
2. APC takes up allergen and presents it epitopes through the MHC II receptor. The APC then migrates to the lymph node
3. The APC activates T-cells to differentiate to helper Th2 cell
4. B cells recognize the allergen presented on the Th2 cell and become activated
5. B cell then differentiates into plasma cells that synthesize IgE antibodies
6. IgE antibodies recognize the allergen, binds to a high-affinity receptor on mast and basophil cells to release histamine, leukotrienes, platelet activation factor (PAF), proteases, heparin and other mediators of inflammation. IL-4 is released which causes more B cells to differentiate into plasma cells
7. Upon repeat challenge of the same allergen, the allergen binds to the IgE on the mast cell surface resulting in the same release of histamine

Question 10

Phases of allergy response

Answer 10

Immediate response: caused by direct effects on blood vessels and smooth muscle of rapidly metabolized mediators such as histamine and heparin released by mast cells. Short, limited exposures often produce an isolated early-phase response

Late phase response: caused by the effects of an influx of inflammatory leukocytes attracted by chemokines and other mediators released by mast cells.

Longer, more intense exposures may produce both early and late phase responses.

Question 11

Anaphylaxis

Answer 11

defined as a serious allergic or hypersensitivity reaction that is rapid in onset and may cause death. Usually involves some combination of two or more of the following: sudden onset of illness with swelling of skin or mucosa, lowered blood pressure, difficulty breathing, or vomiting.

Question 12

Histamine Antagonists

Answer 12

Epinephrine/adrenaline: physiological antagonist of histamine (counteracts histamine) but binds to the adrenergic receptor.

Epinephrine helps anaphylaxis by two routes:

1. alpha-1 adrenergic effect: vasoconstriction to decrease mucosal edema, relieving upper airway obstruction, increases BP
2. beta-1 adrenergic effect: increased rate and force of cardiac contractions, increase bronchodilation, decrease release of histamine, proteases, heparin and other mediators of inflammation from mast cells and basophils

Question 13

H1 antihistamines

Answer 13

Strong evidence base for use in allergic rhinitis, allergic conjunctivitis and urticaria only

Direct effects: primary action on H1R on mast cells to block histamine binding and decrease vascular permeability and vasodilation.

Secondary effects are downstream effects to lower expression of pro-inflammatory cytokines, these are NF-kb and calcium ion channel dependent

Question 14

First generation antihistamines

Answer 14

sedating (because of cross-reaction with the muscarine-acetylcholine receptors in CNS which is anticholinergic and describes the ability to treat motion sickness), less specificity, crosses BBB, lipid soluble structure. Adverse reactions include sedation, drowsiness, dizziness

Question 15

Second generation antihistamines

Answer 15

non-sedating, more specificity, very little if any CNS effects, lipid and ionic functionality. Many have active metabolites. Lower incidence of adverse events than first generation. Severe side effect is prolonged QT interval.

Question 16

Allergic Drug Reactions

Answer 16

also known as a hypersensitivity reactions, resulting from an over-response of the immune system to the standard dose of the drug. Can lead to very sever tissue damage, which can be organ specific or generalized. Adverse drug effects may take on an allergic-like or pseudo-allergic reactions

Question 17

Steven-Johnson syndrome

Answer 17

Rare, serious disorder of your skin and mucous membranes. Usually is a reaction to a medication or an infection. More commonly associated with drug reactions.

Can be life-threatening

Question 18

SJS Begins with…

Answer 18

flu-like symptoms, followed by a painful red or purplish rash that spreads and blisters. Then the top layer of the affected skin dies and sheds.

Question 19

SJS/TEN

Answer 19

Also known as toxic epidermal necrolysis (TEN), SJS/TEN is a continuous spectrum of disease where TEN is the most serious case with > 30% of body surface area affected

Can lead to visual impairment, scarring, irregular pigmentation. TEN can involve systemic organ failure of kidney, neutropenia, and respiratory failure

Question 20

Factors that increase risk for SJS

Answer 20

viral infections, weakened immune system, personal or family history of SJS and genetic (certain HLA gene, HLA-B 1502)

Question 21

Drugs that can cause SJS

Answer 21

anti-gout (allopurinol), pain relievers (Tylenol, APAP, NSAID), anti-infection drugs (Bactrim), anti-seizures, anti-convulsants, antipsychotics, radiation therapy

Question 22

SJS MOA

Answer 22

Mechanism unknown but thought that it is non-hapten (p-i) activation of cytotoxic T cells attacking keratinocytes

Question 23

Factors Affecting allergic drug response

Answer 23

1. Degree which drug binds to human protein (albumin): carrier protein to drugs
2. Route of administration: parenteral has highest risk in sensitive individuals
3. If the drug contains non-human proteins: Xenobiotic drug

4 .Continuous is more likely than single dosing

5. Composition, Metabolism, and sensitivity of individual as determined by genetics or environmental factors

Question 24

How do you tell if it is an allergic drug response?

Answer 24

1. Observed reaction does not resemble drug’s pharmacological effect.
2. Lag time between first exposure to drug and first reaction. Usually first exposure is a mild reaction
3. If patient has had drug previously, subsequent responses are immediate
4. Reaction to drug can occur with minute amounts of drug
5. Symptoms resemble allergic response
6. Symptoms resolve with discontinuation of drug
7. Allergic reaction can be reproduced with drugs of similar chemical structures

Question 25

Hapten Pathway: Drugs acting as antigens

Answer 25

LMW small molecules with simple structures have relatively low antigenicity but drugs can bind to carrier proteins in plasma or tissue and these drug-protein complexes can be recognized as foreign antigens by APC’s and T cells.

Hapten: The drug molecule that binds to a carrier macromolecule. Also called an incomplete antigen. Newly formed complex is called a hapten-carrier complex

Complete Antigen: Larger protein based drug, like insulin, can also be processed as a foreign antigen

Question 26

Non-hapten Pathway: p-i concept

Answer 26

Drugs that lack hapten characteristics can bind directly and reversibly (non-covalently) to immune receptors and thereby stimulate the T cell

Highly specific reaction because it depends on the expression of a TCR that binds the drug with sufficient affinity to cause signaling

Clinically this concept could explain the sometimes rapid appearance of symptoms without previous sensitizations and the sometimes random immune reaction of drug hypersensitivity

Question 27

Type I MOA

Answer 27

Same as the Immune Response pathway. There are two phases, sensitization and immediate response.

1. Allergen = drug or hapten. Enters the body
2. APC takes up drug/hapten and presents it to epitopes through MHC II receptors. APC moves to the lymph nodes
3. Once in the lymph node the APC activates naive T cells to differentiate into helper Th2 cells
4. B cells recognize the allergen and are activated by Th2 cells to differentiate into plasma cells that synthesize IgE antibodies
5. IgE antibodies recognize the drug/hapten, bind its high-affinity IgE receptor on mast and basophil cells.
6. On repeat challenge by the same drug the allergen binds to the IgE on mast and basophil cell surface resulting in histamine release and IL-4 release to cause more B cell differentiation

Question 28

Type II adverse drug reactions

Answer 28

Because blood cells are involved it often leads to hemolytic anemia, leukopenia and thrombocytopenia.

Results in destruction of host cells by cytotoxic antibodies by two pathways:

1. Opsonization: drug binds cell as hapten, IgG or IgM recognize the hapten/cell surface conjugate. Complement or phagocytes with Fc receptors engage immune cells to phagocytose these cells
2. ADCC: IgG bound to cells direct cytotoxic T cells or NKC to destroy cells.

Drugs known to cause Type II ADR: penicillin, quinidine, quinine, cephalosporins, sulfonamides

Question 29

Type III adverse drug reactions

Answer 29

Caused by antigen-antibody complexes formed in blood which are soluble and not bound to cells, that deposit in tissues

Causes local swelling and redness and presents 7-21 days after insult

Principal mechanism for tissue damage is mediated by complement components

Examples: Arthus reaction and serum sickness (antisera from other species are used in drug preparations)

Question 30

Type IV adverse drug reactions

Answer 30

Not antibody mediated, but rather are T-cell mediated

Often affects the skin, because skin has a lot of T cells

Four classes of Type IV, because the roles of T cells were not fully understood

Require involvement of memory effector T cells that have “seen” the antigen. Memory T cells then secrete inflammatory cytokines and recruit effector cells.

Reactions include local skin reactions that are used to diagnose diseases like TB or mumps

Question 31

Penicillin Allergy

Answer 31

Most commonly reported medication allergy, and most commonly is the IgE mediated type I hypersensitivity reaction

MOA: Penicillins spontaneously degrade to a number of reactive intermediates that act as haptens to covalently bind to tissue and serum proteins.

Question 32

Insulin

Answer 32

Complete antigen therefore can induce an immune response on its own.

ADR more common before advent of recombinant insulin, when insulin was from cow or pig and contained xenocontaminants

Usually mild injection site issues, rare anaphylaxis, especially these days with recombinant human insulin.

Question 33

Pseudo-allergic reactions

Answer 33

ADR with signs and symptoms that mimic immunologic drug allergies but in which immunologic mechanisms have not been demonstrated. Difficult to distinguish clinically

Symptoms do not get worse on repeated exposure however, this defines them from an allergic reaction

Not diagnoseed with skin or in vitro allergy testing

Common drug culprits: radiocontrast agents, opiates, NSAIDs, Vancomycin, local anesthetic agents, chemo agents, mAB and biologic therapies

Question 34

Aspirin and NSAIDs allergic reaction

Answer 34

can cause asthma, rhinitis, urticaria, anaphylaxis etc… Allergic and pseudo-allergic response.
Allergic response is type I IgE mediated, doesn’t happen with aspirin.
Pseudo-allergic response is generally with aspirin.

Question 35

Induction of drug tolerance

Answer 35

Used in hospital setting. Most amenable for reactions that are limited to skin, respiratory tract, GI and cardiovascular. Protocols vary but involve a step-wise incremental dosing of the drug. Induced tolerance is temporary and is only for treatment purposes.