Drugs and allergy Flashcards
1
Q
List some allergic disorders
A
- AR (hay fever)
- Allergic conjunctivitis (pink eye)
- Atopic dermatitis
- Urticaria
- Asthma (infl. of airways)
- Anaphylaxis (multi-organ rxn)
2
Q
What is an allergy?
A
- inflammatory disorder (hyper immune response to allergens)
- Maladaptive immune system response creating memory to antigens
3
Q
What are the key players / immune cells involved in allergic reactions?
A
- IgE
- mast cells
- eosinophils
- dendritic cells
- T-cells (Th1&2)
- B-cells
- plasma cells
4
Q
Describe mast cells
A
- Tissue cells of the immune system found in loose connective tissues, organs, vasculature, nerves, skin, respiratory tract, etc. (not present in epidermal cells, CNS, gastric mucosa)
- They store histamine, interleukins, proteoglycans (ex: heparin) and various enzymes in their granules at cytoplasm
5
Q
When do mast cells release their stored enzymes from the granules? Describe this process
A
Granules are released upon stimulation of an allergen; process called degranulation. This causes:
- increased blood flow and permeability of blood vessels (ie infl. and swelling)
- contraction of smooth muscles (eg: bronchial muscles)
- increased mucus production & fluid secretion
6
Q
What are the effects of granule release in the GI tract?
A
Increased fluid secretion and peristalsis. This causes expulsion of GI tract contents (diarrhea, vomiting)
7
Q
What are the effects of degranulation in the airways
A
Decreased diameter and increased mucus secretion. This causes:
- congestion and blockage of airways (wheezing, coughing, phlegm)
- swelling and mucus secretion in nasal passages
8
Q
What are the effects of degranulation in the blood vessels?
A
Increased blood flow and permeability. This causes:
- increased fluid in tissues causing increased flow of lymph to lymph nodes
- increased cells and protein in tissues
- increased effector response in tissues
9
Q
Mediators of common allergy Sx: what Sx do histamines and prostaglandins (PGs) release from mast cells cause?
A
- tickling
- itchiness
- nose rubbing
- allergic salute
10
Q
Mediators of common allergy Sx: what Sx do histamine and leukotriene release from mast cells, eosinophils, and basophils cause?
A
- sneezing
- runny nose (mucosal secretion)
- post nasal drip
- throat clearing
11
Q
Mediators of common allergy Sx: what Sx do histamine, leukotriene, bradykinin, platelet activating factor (PAF) release from mast cells in the tissue, and eosinophils and basophils in the blood cause?
A
- nasal congestion
- mouth breathing
- stuffy nose (mucosal edema)
- snooring
12
Q
Describe histamine
A
- An “autacoid” (designed to exert its action near the site of release) for self relief
- stored in tissue mast cells and blood basophils
13
Q
Histamine is released by what?
A
- antigens; allergic responses (immediate hypersensitivity)
- drugs: morphine, succinylcholine, radio contrast media
- insect venoms
- physical factors: scratching, cold
14
Q
Describe the histamine H1 receptor
A
- important in allergic disorders: target of “classic” generation 1 anti-histamines
- histamine receptor mediated (mainly) effects:
- contraction: gastric and
resp. smooth muscle - vasodilation (H1, H2)
- increased vascular
permeability (H1) - pruritis (H1)
- increased bronchial
secretions and viscosity
(H1)
- contraction: gastric and
15
Q
Describe the H2 receptor
A
- receptor stimulation mediates gastric acid secretion (H2)
- receptor blockage decreases gut acidity (Ranitidine)
16
Q
Describe the H3 receptor
A
cholinergic neurotransmission (airway)? - negative feedback mechanism: inhibit histamine, NA, and ACh release
17
Q
Describe the H4 receptor
A
Found on eosinophils, neutrophils, TCD4 cells
- Role in immune response regulation
- Chemotaxis of mast cells, eosinophils, neutrophils, cytokine release from T and dendritic cells
18
Q
In a test, Histamine had a triple response when pricked onto skin. Describe
A
- RED area at the site of histamine injection - vasodilation
- WHEAL replaces red area - edema
- bright red FLARE - indirect vasodilation (axonal reflex)
19
Q
Describe allergic rhinitis (AR)
A
- rhinorrhea, plugged nasal passages, itching (eyes, nose, throat), tearing, fatigue, headache
- Can be seasonal (airborne pollen) or perennial (animal dander, old, dust, etc)
20
Q
Describe the prevalence of allergic rhinitis
A
- North america: 20%
- 40% of patients with rhinitis present with asthma
- 70% of asthmatics experience rhinitis
21
Q
AR Tx
A
- AVOIDANCE
- Pharmacotherapy
- Immunotherapy
22
Q
List pharmacotherapy options for AR
A
- Anti-histamines: Chlorpheniramine, diphenhydramine, cetirizine, loratadine, fexofenadine
- intranasal glucocorticoids (fluticasone)
- leukotriene modifiers (monteleukast)
- decongestants (phenylephrine, pseudoephedrine)
- mast cell stabilizers (cromolyn sodium)
- anticholinergic (ipratropium)
- anti-IgE therapy (omalizumab)
- systemic steroids (not a preferred option)
23
Q
Describe immunotherapy for AR
A
Allergen specific immunotherapy; to develop a ‘resistance’ to a specific antigen
24
Q
Actions of H1 receptor antagonism
A
- decreased itching
- decreased vascular permeability
- decreased bronchial secretions
- relaxation of bronchial smooth muscle
- decreased cough receptor stimulation
25
What are additional effects of 1st generation anti-histamines?
Drug examples: diphenhydramine (Benadryl), chlorpheniramine (Chlor-Trimeton)
- 1st generation anti-histamines may also possess non-histamine blockage actions like sedation, atropinic, anti-emetic
26
What are additional effects of 2nd and 3rd generation anti-histamines?
```
Drug examples (2nd gen): Cetirizine, loratadine (Claritin)
Drug example (3rd gen): Fexofenadine (Allegra)
- These two types of anti-histamines also prevent mast cell release of mediators that cause inflammation
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27
Describe the pharmacokinetics of anti-histamines in AR
- Administration rate may be flexible depending on the anti-histamine: oral (allergy), intranasal (allergy), or IV (only later in anaphylaxis; benefit questionable)
- half-lives are variable (8-24h)
- their concentration in breast milk parallels their concentration in plasma
- best if they are taken before an anticipated allergic reaction
- most are metabolized by CYP P450 system (CYP 3A4) and grapefruit juice may block metabolism
28
Indication of anti-histamines
- DOC for mild to moderate rhinitis
- can relieve sneezing, itching, nasal discharge, and ocular Sx (itching, tearing, erythema)
- best for exudative allergies (hay fever)
- for seasonal rhinitis: 1st, 2nd, and 3rd gen anti-histamines are all effective
29
Describe anti-histamine use in conjunction with a decongestant
- may be given with a decongestant (pseudophedrine)
| - for severe AR, use intranasal glucotoricoid
30
Intranasal glucocorticoid drug example
Fluticasone
31
How are 2nd and 3rd gen anti-histamines different than the 1st gen?
Lack sedative effects
32
Adverse effects of 1st-gen anti-H's (Chlorpheniramine, diphenhydramine)
- atropinic, somnolence, problems with congnition, learning and memory, psychomotor, etc.
- No longer approved in Canada for kids under 2. Use limited for kids under 6
- not recommended during pregnancy (Although 2nd and 3rd gen are safe)
33
Adverse effects of 2nd and 3rd gen anti-histamines (Cetirizine, loratidine, fexofenadine)
- penetrate BBB poorly so sedation not an issue (although some with Cetirizine; 10% of patients)
- fexofenadine is free of sedation
- Cetirizine has demonstrated long-term safety in children
- intranasal administration gives a rapid onset (Drug: Azelastine)
34
Describe fluticasone
- effective for nasal and ocular Sx, itching, sneezing, discharge, congestion
- most effective for prevention and Tx
- DOC for moderate to severe disase
- dosing at plateau of dose-response curve (increasing the dose increases the SE's but not the benefits)
35
Describe the use of fluticasone (intranasal glucocorticoid)
- effective used once daily
| - may take 7 days to be maximally effective
36
SE's of fluticasone
- might cause epistaxis (nose bleeds)
- not well studied for SE's associated with intranasal administration (newer ones safer?)
- systemic glucocorticoids have effects on growth, bone density, cataract formation, intraocular pressure, etc.
37
Leukotrienes are mediators of what effects?
- bronchiole constriction
- mucous secretion
- infl. of airway
38
Prostacyclin, PGs, Thromboxanes are mediators of what Sx?
- pain
- fever
- inflammation, etc.
39
Corticosteroids inhibit what two pathways?
1) Inhibits Phospholipase A2 from converting membrane lipids into arachadonic acid (AA), thus leading to the formation of LT's, PG's, Prostacyclin, Thromboxanes
2) Inhibits the protein synthesis of COX-1 and -2 enzymes. Cylooxygenase leads to the formation of Prostacyclin, PG's and Thromboxane
40
Give a drug example of a Leukotriene receptor antagonist
Monteleukast
41
Describe the purpose, use and effectiveness of Leukotriene receptor antagonists
- LT's are released during allergic infl. by mast cells, eosinophils, basophils, inflammatory cells
- LT's are involved in infiltration of inflammatory cells, mucus secretion, but also affect airway constriction
- Monteleukast provides modest relief of congestion, itching and discharge
42
LT-receptor antagonists (Monteleukast) are normally used with what?
- Used with anti-histamine or intranasal glucocorticoid
| - less effective than intranasal glucocorticoids
43
What receptor does phenylephrine target for what effect?
- targets alpha-1 receptor (agonist effect)
| - leads to increased vasoconstriction and hence reduced nasal swelling
44
Phenylephrine relieves what Sx?
relief of congestion only; not helpful for sneezing, itching, discharge.
45
Compare phenylephrine and pseudoephedrine as decongestants
- Phenylephrine has largely replased pseudoephedrine, which can't be sold alone
- many side effects: insomnia, nervousness, ,headache, palpitations, HTN, etc
- topical intranasal application leads to fewer systemic effects
- use for over 3 days can lead to rebound congestion
- pseudoeph. proven to be effective, but not phenyleph.
46
Drug example of a mast cell stabilizer
cromolyn sodium
47
Describe mast cell stabilizers and their MOA, effects
- Mast cell stabilizers inhibit degranulation and the release of infl. mediators (histamine, LT's, PG, PAF)
- less effective than intranasal corticosteroids
- must be given before exposure
- almost no local/systemic toxicity
48
List an anticholinergic drug used in AR. What's its MOA? Effects?
Drug: Ipratopium (anti-muscarinic)
- reduces mucus secretion with no effect on inflammation (so no relief of sneezing, itching, congestion)
- useful if primary Sx is nasal discharge
- SE's: atropinic-like effects (dry mucus membranes, urinary retention, etc.)
- caution in glaucoma and prostatic hypertrophy
49
Give a drug example of an anti-IgE antibody. What its MOA and effects?
Drug: Omalizumab
- given as SC injection
- selectively binds iGE
- prevents igE from binding to cells and reduces free IgE in serum
- anaphylaxis risk in 0.1% of patients (hours or days later)
50
Immunotherapy is usually administered over what time period?
- Initial build-up period where the patient goes for weekly then monthy injections for years
- dose is increased until fewer Sx are achieved with natural exposure
- once desired dose is established; monthly maintenance injections necessary
- Administered over 3-5 years; benefit may continue when admin is discontinued
51
Indications for immunotherapy
- IgE in serum or skin sensitivity to allergen (cat, dog, pollen, etc)
- poor pharmacotherapy response or side effects
- patient preference
52
When should you avoid immunotherapy?
in severe asthma, CV disease, high dose beta blockers.
| - do not initiate Tx during pregnancy
