Flashcards in CPTP 3.13 Drugs used in Inflammation Allergy and Pain 1 Deck (32)
Through which route is emergency adrenaline given during anaphylaxis?
What does 1:1000 solution mean in drug calculations?
1g in every 1000ml (revise drug calculations)
= 1000mg in 1000ml
= 1mg in 1ml
What are local hormones called? What do these include?
Name the eicosanoids
Where are autocoids produces?
In the same tissue they act on, in many tissues (not specific glands)
Do autocoids have a systemic effect? Give an example
Only if large amounts are produced and are moved to the circulation.
Anaphylaxis is caused by a systemic-wide increase in histamine
Where are autocoids metabolised?
Metabolised locally and have a short duration of action
Where does most histamine synthesis occur? Which cells produce it and where is it stored?
Where the body comes into contact with the environment:
• GI tract
• Brain (histaminergic neurones)
Which cells in the skin and lungs create histamine and where is it stored?
Produced by mast cells and basophils, and stored in their granules
Which cells in the GI tract create histamine?
Enterochromaffin-like (ECL) cells
What does histamine bind to? What does each of these receptors mediate?
H1: Inflammatory and allergic reactions
H2: Gastric acid secretion
H3: Presynaptic receptors (inhibit release)
What is the effect of Histamine on the following, and what receptor mediates this:
2) Vascular smooth muscle?
3) Vascular endothelium
4) Peripheral nerves
What is the clinical manifestation of each?
1) Bronchoconstriction, H1
2) Vasodilation, H1
3) Contraction and separation of endothelial cells (creating fenestrations), H1
Pain & Itch:
4) One of many to sensitise multimodal nerves, H1
5) Increase in HR and contractility, H2
Peptic ulcers, heartburn
6) Increases gastric acid secretion, H2
7) Neurotransmitter, H3
In histamine-mediated vasodilation, which vessels are affected?
The following dilate:
• Postcapillary venules
• Terminal arterioles
What molecules does H1 receptor stimulation lead to the increased expression of?
• Release of cytokines
• Release of eicosanoids
• Expression of endothelial adhesion molecules
• Activates NFKB (K=kappa)
What is NFKB?
A potent pro-inflammatory transcription factor, for innate immune responses
Which immune and inflammatory pathological processes are mediated by histamine?
• Atopic dermatitis
• Bronchospasm (Asthema)
• Allergic rhinitus
What are hypersensitivity reactions?
Allergic reactions due to IgE production against environmental agents (e.g. pollen)
• Allergic asthema
• Allergic rhinitis
• Food or drug allergy
• Anaphylactic shock
• Urticaria (hives) or eczema
What causes hypersensitivity? Describe this process.
Prior sensitisation to an allergen:
• Initial exposure causes B cells to produce 'allergen-specific' IgE antibodies
• These allergen-specific IgE antibodies bind to the surface of mast cells and basophils
• Subsequent exposure to the allergen binds to the IgE, causing crosslinking of mast cells
• The mast cells 'degranulate', releasing their mediators (i.e. histamine)
How is urticaria and rhinitis most commonly treated?
What are other uses for this?
• H1 antagonists
Sedatives (first-generation antihistamines) and anti-emetics (for motion sickness)
What is the difference between first and second generation antihistamines? Give the formulary example of each.
First generation (Chlorphenamine):
• Charge neutral at physiological pH
• Therefore readily cross blood-brain barrier
• Blocks histaminergic actions in the CNS (drowsiness)
• Less selective for H1 and may also bind:
> Cholinergic receptors
> a-adrenergic receptors
> Serotonergic receptors
• Ionised at physiological pH
• Therefore they cannot cross the BBB
What IS anaphylaxis? (at last.)
Short for anaphylactic shock (type of shock) in response to massive histamine release. This is what happens:
• Widespread increase in vascular permeability
• Constriction of airways
• Laryngeal oedema (which can cause suffocation)
How is anaphylaxis treated?
Steps in order:
1) Stop administration of the antigen (food or drug)
2) Administer adrenaline IM (usually 0.5mg which is 0.5ml of 1:1000 solution)
3) Give the patient oxygen
4) IV fluids if hypotension still present
5) Administer parenteral H1 antagonist chlorphenamine
6) Administer glucocorticoid hydrocortisone
What are the effects of adrenaline when administered to treat anaphylaxis? Which receptors are these effects mediated by?
• Combats hypotension/shock
• Increases HR and force
• Combats hypotension/shock
• Decreases wheezing
Why is a glucocorticoid administered during anaphylaxis treatment?
Some anaphylaxis events have a 'biphasic response' because as a result of the histamine release, a number of immune cells are recruited, which takes time to initiate due to gene transcription.
This can create a second 'wave' of anaphylaxis which can be prevented by glucocorticoids
How do glucocorticoids have their anti-inflammatory effects?
They decrease the production of prostaglandins and leukotrienes
What type of receptor is H1?
What states can it be in?
Gq protein coupled
It is in an equilibrium between active and inactive
• Active: GTP-bound
• Inactive: GDP-bound
They are 'constitutively active':
• In the basal state, where an agonist is not bound, the receptor tends towards ACTIVATION
What does activation of Gq cause?
• Activation of phospholipase C
• IP3 and DAG release
• PKC activated
• Proteins are phosphorylated
• Intracellular Ca2+ is released
This increase in intracellular Ca2 will create the symptoms of anaphylaxis:
• Bronchospasm through calmodulin
• Smooth muscle relaxation through NO synthesis causing ERYTHEMA
Describe H1 receptor when bound to histamine, when bound to H1 antagonists, and when unbound.
(IMG 7) Unbound:
• 'Constitutively active' this means that in the basal state, the receptor is slightly active
Bound to histamine:
• When histamine binds, the equilibrium is shifted so that even more H1 receptors are active
H1 antagonists (antihistamines):
• Bind preferentially to the inactive confirmation of the H1 receptor, thus shifting the equilibrium to the inactive state
What are H1 antagonists more accurately referred to as?