Lecture 8: OTC Allergy and Insomnia Flashcards
What is the difference between first generation and second generation antihistamines?
First generation has an impact on wakefulness, not targeted toward allergy efficacy
What are allergies?
A hypersensitivity of the immune system to typically harmless substances in the environment
What can allergies include?
- Hay fever
- Food allergies
- Atopic dermatitis
- Allergic asthma
- Anaphylaxis
What are the symptoms of allergies?
- Red eyes
- Itchy rash
- Sneezing
- Runny nose
- Shortness of breath of swelling
What is Hay fever?
A form of allergic rhinitis
What is Rhinitus?
A reaction that occurs in the upper respiratory tract that leads to nasal congestion, runny nose, and sneezing
Which antibodies do the anaphylactic reaction involve?
Immunoglobulin E antibodies (IgE)
What causes anaphylaxis?
- 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 the release of inflammatory chemical such as histamine
What is a Type One allergic reaction?
Anaphylaxis
What are OTCs more geared towards?
The type two, three and four hypersensitivity reactions that are slightly more delayed in their onset
What kind of receptors are Histamine receptors?
G protein coupled receptors
What are the four classes of Histamine receptors?
H1
H2
H3
H4
What do H1 receptors play a role in?
The allergic response
Where are H1 receptors locasted?
- Smooth muscle
- Vascular endothelial cells
- In the heart
- In the CNS
What does activation of H1 receptors do?
- Increases vascular permeability
- Vasodilation
- Stimulation of sensory neurons producing cough
- Smooth muscle contraction of the bronchi
- Eosinophilic chemotaxis (eosinophils migrating to tissues)
What directly underlies histamines ability to cause vasodilation?
H1 receptors on vascular endothelial cells
Where in the brain are histamine receptors expressed with high density?
In regions involved in arousal and waking (thalamus, cortex and noradrenergic, serotonergic, and dopaminergic nuclei)
What is histamine an important neurotransmitter in?
The wake-promoting system
Which neurotransmitters promote sleep?
- GABA
* Galanin
What are the wake promoting neurotransmitters?
- Histamine
- Serotonin
- Norepinephrine
Which part of the brain is associated with wake promoting?
The Thalamus
Why do many antihistamine drugs have an effect on alertness?
Because histamine in the CNS drives wakefulness
What is the first generation antihistamine?
Diphenhydramine
What kind of effector mechanism does Diphenhydramine have?
It is an inverse agonist at the H1 receptor
Which receptor does Diphenhydramine target?
The H1 receptors
What does Diphenhydramine do?
It blocks the effects of histamine in blood vessels and smooth muscle cells reducing allergic reaction symptoms
How does Diphenhydramine affect the brain?
- It crosses the blood-brain-barrier and inversely agonizes the H1 receptors in the CNS resulting in drowsiness
- Suppresses the medullary cough center
What is an inverse agonsit?
A drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist
What are the effects of a neutral antagonist?
A neutral antagonist has no activity in the absence of an antagonist or inverse agonist, but can block that activity of either
Which G receptor pathway does histamine induce?
The Gq pathway
What is Diphenhydramine marketed as?
- OTC allergy drug
* OTC sleep aid
In addition to their activity at the H1 receptors, what do first gen antihistamines bind to?
Other receptors
What can the binding of first gen antihistamines do?
Contribute to off-target side effects
What does the inhibitory constant (Ki) describe?
How well an antagonist or inverse agonist binds to a receptor (affinity)
How is Ki measured?
With fluorescently labeled competitive binding assays. A receptor bound to or expressed by a bunch of cells or the receptor itself bound to a plate and add a fluorescently labelled ligand with a known binding efficiency and saturate those receptors with a ligand. Then introduce increasing concentrations of the chemical of interest. As the conc. increases, you’d essentially wash away the original ligan until none of it is bound. So there is a decreasing level of fluorescence. The Ki is determined when 50% of the fluorescence disappeared
What is the Ki in numbers?
The concentration of the drug that displaces 50% of the labeled ligand
What does a Low Ki mean?
That the drug has a high affinity
What is the cause of virtually all unwanted side affects?
Drugs binding to different receptors
What is required for all drug effects?
Ligand receptor interactions
Which receptors do first generation antihistamines (diphenhydramine) bind with high affinity to?
Muscarinic cholinergic receptors
What is meant by first generation antihistamine (diphenhydramine) bind with high affinity to muscarinic cholinergic receptors?
They have anticholinergic effects
What side effects can first gen antihistamine (diphenhydramine) have when binding to muscarinic cholinergic receptors?
- Dry mouth
- Constipation
- Confusion
Other than H1 receptors, which type of receptors do first gen histamines bind to?
Muscarinic cholinergic receptors
Why does diphenhydramine usually bind H1 receptors at its recommended dosage?
Because it has high affinity for H1 receptors
What is pKi?
The negative log of Ki
Why is only H1 targeted under normal circumstances with first gen antihistamines?
Because the amount of diphenhydramine administered is controlled and it doesn’t reach high enough concentrations to start producing off target effects
What tolerance of diphenhydramine develops?
Tolerance to the sedative effects
How does the use of sedative antihistamine affect sleep?
They decrease the quality of sleep (less time in REM, more time in light sleep) so less restorative
What can long term use of sedative diphenhydramine be associated with and why?
Dementia and Alzheimer’s due to anticholinergic effects
What is the breakdown of cholinergic pathways in the brain linked to?
Cholinergic neuron death, alzheimer’s and dementia
What is Tolerance?
Needing more drug to get the same effect
What are the second gen antihistamines?
- Loratadine
- Cetirizine
- Fexofenadine
What is the difference between first and second gen antiistamines?
Second gen antihistamines have higher selectively for the H1 receptors
Why do second gen antihistamines lack the sedative (drowsy) effects?
Because they have poor BBB permeability
Why do second gen antihistamines need fewer doses?
Because the have a longer duration of action
Why do second gen antihistamines have much higher selectivity for H1s?
Because they have none of the same off target binding
What are the improvements that second gen drugs have?
- They are highly H1 selective
- There is virtually no binding to cholinergic and serotonergic receptors
- Limited BBB barrier crossing
- Not eliminated as quickly
What does Cetirizine do at H1 receptors?
Cetirizine is an H1 receptor antagonist
Why does Cetirizine produce minimal sedation effects?
Because it has poor BBB permeability
What is the duration of action of Cetirizine?
Around 24 hours
What does Loratadine do at a receptor?
It is an inverse agonist at the H1 receptor
What is Loratadine usually bound to?
Plasma proteins (albumin)
What is the activity of Bound proteins?
Bound proteins/drugs are not active
What kind of drugs cannot exert pharmacological effects?
Protein bound drugs
What must a drug that is bound need to do in order to exert pharmacologic effects?
They must become free drug
What can free drug do?
Leave the blood and enter the tissue and bind its therapeutic target
What is the form of drug that is available for clearance and elimination?
Free drug
What will extend the duration of action?
A drug being highly protein bound
What happens when Loratadine is given orally?
First pass metabolism converts it into desloratidine
What does Desloratadine do in comparison to Loratadine?
Carries most of the anti-histamine effects (therefore is a prodrug)
Because Loratadine undergoes first pass metabolism what is it know as?
A prodrug
What is the difference in half life of Loratadine and Desloratadine?
Desloratadine has a half life of 27 hours and Loratadine has a half life of 8 hours
What carries most of the antihistamine effects, Loratadine or Desloratadine?
Desloratadine
What are Prodrugs?
Drugs that must be converted into their active form via liver metabolism
How does Loratadine work in terms of the BBB?
Loratadine has poor penetration of the BBB so it does not have sedative effects
What kinds of enzymes does the liver express?
CYP enzymes
Which binds plasma proteins Desloratadine or Loratadine?
Desloratadine does not bind to plasma proteins but Loratadine does which is why Desloratadine distributes quicker
