Lothstein - Anti-Histamines Flashcards
1
Q
What are the sites of histamine sythesis?
A
- L-histidine -> histamine
- Mast cells and basophils have ability to store large amts of histamine (in granules) for its release, when needed
- Control of release in many other cells, but only at the level of conversion of histidine to histamine:
1. Epidermal cells, intestinal mucosa, CNS neurons, rapidly-dividing cells
2
Q
What are the 4 primary functional sites of histamine?
A
- Stomach: stimulate production of HCl
- Brain: neurotransmitter -> regulates sleep, hormonal secretion, memory formation, brain arousal (absence of histamine in brain can make you sleepy)
- Immune system: acts as vasodilator in allergies/immune system response
- Role in vasculature and smooth mm focus of the lecture
3
Q
Briefly describe the importance of the histamine receptors.
A
- Histamine, by itself, has no function -> it has to bind to a receptor
- H1 was the first to be identified
- Roles of histamine can be segregated by the type of receptor it is interacting with (see attached):
1. H3 believed to control release of histamine from a number of cells
2. H1/2 also involved in CNS
3. Focus on H1 antagonists -> no FDA approved drugs out for H3-H4 antagonism yet (H2 antagonists used for GI biz)
4
Q
What are the functions of the different histamine receptors?
A
- Distinct and overlapping functions
- All 4 receptors can be linked to a variety of nasal symptoms in rhinitis and allergies -> H1 is most important in this regard
5
Q
How can one ligand target multiple receptors?
A
- Molecules in the body have a complex topology that can often be recognized by different types of receptors
- Histamine can bind 4 different histamine receptors, and other receptors as well -> basis of AE’s and side effects
6
Q
How is histamine release by mast cells controlled?
A
- Latticework of (-) charged carbs bound to the (+) charged histamine (and other pro-inflammatory cytokines, i.e., LT’s)
- Histamine has a short half-life (prevents systemic effect) -> time-release capsule whereby sodium exchanges with histamine, which is is gradually released
1. Allows a broader release area of histamine in the body, producing a local-regional effect, rather than an extremely local effect - Mast cell not destroyed by release -> granules fuse w/PM and release their contents
1. Takes several days for mast cells to regenerate their supply of histamine
7
Q
Describe the effects of histamine on the vasculature.
A
- Histamine only has effect where there are histamine receptors -> none in the true capillary bed (permeability actually in the VENULES/ARTERIOLES: VASODILATION)
-
H1 (aa and vv): constriction of vessel via smooth mm, but dilation at endothelial level -> net effect on LG VESSELS is VASOCONSTRICTION (smooth mm effect predominates)
1. This is true in vasculature, and also bronchi (net effect in the lungs is BRONCHOCONSTRICTION) - H2: slower onset, and more persistent VASODILATION in SM VESSELS -> allows immune system components to move into tissue and confront and destroy allergens (at consequence of itching, sneezing, and runny nose)
8
Q
What happens when a mast cell responds to an allergen?
A
- Mast cells sensitized by IgE, so when an allergen binds, there is a cross-linking of IgE bound to specific receptors, leading to activation of mast cell and histamine release
- Other substances involved/released from mast cells: LT’s, PG’s, tryptase (but about 1,000,000x more histamine)
- Histamine mostly involved in the early phase allergic response (sneezing, itching, runny nose/rhinorrhea, nasal obstruction -> fluid, swelling due to edema)
1. This stage is the target of anti-histamines - Late response: runny nose, watery eyes
9
Q
How do anti-histamine drugs work?
A
- Unclear, but the proposed mechanism is inverse agonism
- Receptors exist in active and inactive conformation, and activity depends on % of receptors in e/conformation
- Histamine stabilizes the # of receptors in the active conformation
1. All H1 antagonists can bind the inactive form, and accumulate this conformation, decreasing histamine receptor activity - Technical difference pharmacologically, but the same effect clinically as competitive inhibition
10
Q
What is the general H1 antagonist structure?
A
Substitutions on these 3 sites for the drugs
11
Q
What are the therapeutic applications of H1 antagonists?
A
- Amelioration of allergy and hay fever symptoms
- Treatment of symptoms of insect bites and stings
- Treatment of symptoms of contact flora poisoning
- Attenuation of motion sickness and vertigo (1st gen -> NOT through interaction with histamine receptors, but rather via anti-cholinergic effects)
12
Q
Compare and contrast the 1st and 2nd gen anti-histamines (table).
A
-
1st gen: 4-6 hour duration, so pt compliance can be a limiting factor
1. Anticholinergic effects can be beneficial or AE’s. - 2nd gen: upwards of 24 hour duration
13
Q
What are the properties of the 1st gen H1 antagonists?
A
- Common functional effects: can almost ignore structural categories; some variations in sedation, but all are sedative
-
Sedative effect: H1 receptors in hypothalamus; histamine is a potent regulator of wakefulness and sedation in the brain -> presence of histamine makes you more alert
1. Drugs pass through BBB (uncharged) -> can bypass P-gp’s, and easily penetrate brain/have CNS effects -
Anti-cholinergic: no such thing as a truly specific agonist or antagonist -> as you INC dose, drug will be able to bind o/receptors, in this case, muscarinic
1. GI effect is in H2 receptor domain (smooth muscle peristalsis -> mild effect of 1st generation meds)
2. Contraindicated for the tx of asthma bc dry and thicken mucosal secretions (anti-cholinergic) - No effect on histamine release from mast cells
14
Q
What are the names and indications of the ether/ethanolamine derivatives?
A
-
Diphenhydramine and Dimenhydrinate: allergic rhinitis, anaphylaxis
1. Adjunct, common cold, insomnia, motion sickness
2. Highly sedating -
Clemastine: allergic rhinitis, cutaneous hypersensitivity, uticaria, and angioedema
1. Highly sedating - 1st gen: CONTRAINDICATED IN ASTHMA PATIENTS
15
Q
What are the names and indications of the alkylamine derivatives?
A
- Chlorpheniramine: allergic rhinitis, common cold
- Brompheniramine: allergic rhinitis, urticaria
- 1st gen: CONTRAINDICATED IN ASTHMA PATIENTS
19
Q
What are the AE/side effects of the 1st H1 antagonists?
A
- 1st-generation antagonists are not only targeting the H1 receptor, but can bind, to a lesser extent, other receptors
- Motion sickness treatment is a consequence of muscarinic effects (not H1)
1. CN VIII -> inner ear and vomit reflex -> block muscarinic transmission through this N - Also have sedative effect
20
Q
What are the properties of the 2nd gen H1 antagonists?
A
- Don’t cross BBB nearly as much as 1st gen (bc charged): 70% 1st gen to 20% 2nd gen -> limited to no sedation
- All have the same effect
- Comparable potency to 1st gen for H1 receptor blocking, but NO sedative or anti-cholinergic effect
1. Little effect on smooth mm peristalsis in the GI tract - NO effect on bronchial secretions, so can be taken safely by asthma patients (but not first-line asthma drugs).
- Single dose over 24 hours due to pharmacokinetics; un-metabolized (or metabolized to another active form) by liver and secreted in feces or urine
-
Note: 2 no longer on market due to interaction with anti-fungals/macrolides leading to fatal cardiac arrhythmias (K channel binding) -> always think about drug combos
1. Short hx of FDA warnings for use of 2nd gen anti-histamines, but most were IV abuse drugs -> no drug is absolutely safe bc every individual has potential to be different in terms of their response to a drug
24
Q
What are the goals of 3rd gen H1 antagonist drug development?
A
26
Q
What are the clinical uses of the H1 antagonists, 1st gen vs. 2nd/3rd?
A
- Note: role of cholinergic receptors in itching dermatosis, so first generation have more of an effect
