Lecture 12: Over The Counter Medication (Allergy and Insomnia) Flashcards
What are allergies?
allergies are conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment
include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis
symptoms include red eyes, itchy rash, sneezing, runny nose, shortness of breath or swelling
How does the allergy mechanism involve immunoglobin E antibodies (IgE)?
B cells react inappropriately to an allergen to produce IgE antibodies against the allergen
antibodies bind to a receptor on mast cells or basophils
subsequent exposure to the allergen triggers release of inflammatory chemicals such as histamine
What are histamine receptors?
histamine receptors are G protein coupled receptors
there are four main classes (H1, H2, H3, H4)
H1 receptors play a prominent role in allergic response
What are H1 receptors?
H1 receptors are located in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system
activation of the H1 receptor causes increase vascular permeability, vasodilation, stimulation of sensory neurons producing cough, smooth muscle contraction of the bronchi, and eosinophilic chemotaxis
histamine H1 receptors occur throughout the brain, with particularly high density in regions involved in arousal and waking (thalamus, cortex, and noradrenergic, serotonergic, and dopaminergic nuclei)
thus, histamine is an important neurotransmitter in the wake-promoting system
What are the mechanisms involved in diphenhydramine first generation antihistamines?
diphenhydramine is an inverse agonist at the H1 receptor (it blocks activity at the H1 receptor)
an inverse agonist is a drug that suppresses endogenous receptor signaling; an inverse agonist will behave as an antagonist in the presence of an agonist (e.g. histamine)
it blocks the effects of histamine in blood vessels and smooth muscles cells reducing allergic reaction symptoms
diphenhydramine readily crosses the blood-brain-barrier (BBB) and inversely agonizes the H1 CNS receptors, resulting in drowsiness
it also suppresses activity in the nucleus tractus solitarus
How are first generation antihistamines marketed?
diphenhydramine is marketed as an OTC allergy drug (Benadryl)
also marketed as an OTC sleep aid (e.g. Nytol)
included in many cough and cold formulations (e.g., Tylenol Complete Cold, Cough and Flu)
What is competition in relation to drugs?
drugs must bind to an effector protein (receptor, enzyme, etc) to have an effect
drugs compete for occupancy with endogenous ligands
endogenous ligands are almost high efficacy, low affinity agonists
drugs that are agonists amplify the endogenous ligand effects; drugs that are antagonists reduce endogenous ligand effects
What is the relationship between affinity and EC50?
interaction between ligand and effector protein is random
but how long the ligand stays bound to the effector protein dependent on the affinity between ligand and receptor
EC50 reflects the concentration of drug needed to occupy half the effectors; drugs with high affinity need less drug to occupy effectors, because they stick on longer
each receptor-ligand pair will have a unique affinity (KD or Ki)
What is the competition between diphenhydramine and histamine?
in the case of antihistamines, diphenhydramine competes for binding at the H1 receptor with histamine
diphenhydramine and histamine have similar affinities to the H1 receptor (~10nm), so need relatively high doses of diphenhydramine to block histamine effects (25-50mg per day)
What is the affinity of first generation antihistamines?
in addition to their activity at the H1 receptor, first generation antihistamines (like diphenhydramine) also bind to other receptors with lower affinity (e.g., diphenhydramine is selective for H1, not specific)
this can contribute to off-target side effects
how well an antagonist (or inverse agonist) binds to a receptor (aka affinity) can be described by the inhibitory constant (Ki)
How is a drugs inhibitory constant (Ki) determined?
the Ki is determined using competition assays with a known labeled ligand and the antagonist of interest
Ki = the concentration of drug that displaces 50% of the labeled ligand
low Ki = high affinity
pKi is just the negative log Ki (like pH); so a drug with high affinity with have high pKi (and low Ki)
Ki reflects the affinity of the antagonist
What are the side effects of first generation antihistamines?
first generation antihistamines (like diphenhydramine) bind with relatively high affinity to muscarinic cholinergic receptors (have anticholinergic effects)
this leads to side effects such as dry mouth, constipation, and confusion
older individuals are particularly susceptible and should generally avoid
What are some issues associated with diphenhydramine first generation antihistamines?
tolerance develops rapidly to the sedative effects of diphenhydramine
use of sedative antihistamines also decrease the quality of sleep (less time in REM, more time in light sleep, less restorative)
long term use may be associated with dementia and Alzheimer’s (due to the anticholinergic effects)
What are second generation antihistamines?
second (and third) generation antihistamines have higher selectivity for the H1 receptors
second generation anti-histamines have poor blood-brain barrier permeability, so lack the sedative (drowsy) effects
also these drugs have longer duration of action (so need fewer doses)
What are the mechanisms involved in cetirizine second generation antihistamines?
cetirizine is an H1 receptor antagonist
it has poor blood-brain barrier permeability, so produces minimal sedation compared to first generation antihistamines
duration of action is around 24 hours (compare to diphenhydramine with duration of action of 4-6 hours)
