drugs and histamine receptors Flashcards
What 4 conditions occur when inflammation goes wrong?
- Anaphylaxis
- Asthma
- Rheumatoid arthritis
- Atherosclerosis
Which step of inflammation do medicines such as steroid, antihistamines and anti-inflammatory drugs target?
Release of chemical mediators
Which 2 mediators cause vasodilation?
- Histamine
- Prostaglandins (PGE2 & PGI2)
Which 2 mediators cause increased vascular permeability?
- Histamine
- Platelet activating factor (PAF)
Which 4 mediators cause exudation (fluid filtering from circulatory system into the surrounding tissue)?
Plasma proteins:
- Complement
- Coagulation system
- Fibrinolytic system
- Kinin system
What are the 7 principle mediators/autocoids/local hormones of inflammation and allergy?
- Histamine
- Platelet Activating Factor
- Bradykinin
- Nitric Oxide
- Cytokines (interleukins, interferons, chemokines, colony stimulating factors)
- Eicosanoids (prostagladins, thromboxanes, leukotrienes)
- Plasma proteins (kinins, complement, coagulation and fibrinolytic factors)
When are these mediators released?
From cells upon stimulation
How is histamine synthesised?
Decarboxylation of histamine by L-histadine decarboxylase
Which 2 enzymes rapidly metabolises histamine?
n.b. they produce two different products
Histamine-N-methyltransferase
or
Diamine oxidase/histaminase
How many different types of histamine receptor subtypes have been discovered?
4
Which two types of celLs contain histamine contained in granules?
- Mast cells
- Basophils
Which cells in the gastric glands in the gastric mucosa are also found to contain histamine?
Enterochromaffin-like cells (ECL)
In which organs of the body can the highest levels of histamines be found?
Lung
Skin
Brain
GI tract
n.b. they are found throughout the body too!!
Where are mast cells produced?
Bone marrow
(released as immature cell and matures in the tissue)
Which antibody does the FCERI receptor have a high affinity for?
IgE
What are the 4 stages of mast cell degradation?
- Priming of mast cells (body produced IgE = bind mast cells = chemical mediator release)
- 2nd exposure to allergen = IgE bind to mast cell surface
- Activates mast cell (granule movement and fusion to membrane due to increased Ca)
- Degranulation (release of chemical mediators)
Which two other factors can activate mast cells?
Complement components:
C3a
C5a
Which process gets the complement & phagocytes present mainly in the blood to the site of tissue invasion?
Inflammatory response
What 2 things can cause histamine release?
- Some neuropeptides (e.g. substance p)
- certain basic drugs (e.g. morphine & tubocurarine)
n.b. some basic drugs e.g. morphine and other opioids can displace histamine from mast cells without activating cell surface receptors
What inhibits histamine release?
An increase in cAMP
e.g. by beta adrenoreceptor agonists
What are the 3 physiological roles of histamine?
- local immune response (tissue repair, inflammation, control of local blood flow, allergies & anaphylaxis)
- regulates physiological function in the gut (increased gastric acid secretion = H2)
- Neurotransmitter in CNS
Why is the reaction to histamine location dependant?
- different histamine receptors
(all GPCRs) = H1, H2, H3 & H4
(located in different tissues & couple different G proteins)
What type of receptor is the H1 receptor?
And where is it found?
GPCR - Gq
= activates PLC & PIP2
Found in smooth m, endothelium & CNS tissue
Activation of the H1 receptor causes (8):
- Bronchial smooth muscle contraction
- vasodilation
- separation of endothelial cells
- increased vascular permeability
- pain and itching
- motion sickness
- allergic rhinitis
- sleep and appetite suppression
What are H1 receptor antagonists used for?
- Treat allergy (hay fever, urticaria)
- Treat nausea and vomiting
How H1 receptor antagonists drugs taken?
Where are they metabolised?
Orally
Hepatic metabolism
Name 3 1st generation H1 receptor antagonists?
- Mepyramine
- Promethazine
- Diphenhydramine
What is the average duration of effect for H1 receptor antagonists?
Approx 4-6 hours
What is promethazine used for (4)?
- Allergic disorders
- Nausea and vomiting
- Insomnia
- Sedation
What is Diphenhydramine used for (4)?
Antihistamine with:
- Anticholinergic
- Antitussive (prevents coughing)
- Antiemetic (prevents nausea)
- Sedative
What are the 2 benefits of 2nd generation over 1st generation H1 receptor antagonists?
- less CNS depression (non-drowsy)
- Last longer (12-24 hours)
What are the 4 different 2nd generation H1 receptor antagonists?
- Fexofendine
- Cetirizine
- Loritadine
- Cinnarizine
What is fexofendine used to treat (1)?
Seasonal allergic rhinitis
What is ceterizine used to treat (4)?
Hay fever
Allergies
Angioedema = swelling of deeper layers of skin
Urticaria (hives)
What is Loratadine used to treat (1)?
Allergies
What is Ciinnarizine used to treat (2)?
Motion sickness & vertigo
(also contains Ca T-type channel blocker)
In which neurones are high concentrations of histamine and histamine decarboxylase found?
Hypothalamus
What are the effects of Histamine as a neurotransmitter?
Arousal (alertness)
Sleep (quality)
Circadian Rhythm
From which nucleus of the hypothalamus is histamine released?
Tubermammillary nucleus
What causes motion sickness?
The disagreement between visual perceived movement and the movement detected by the vestibular system
- Same effect from neurotoxins= stimulates H1 receptors in the nucleus solitary tract = vomitting
How to antihistmaine (H1) drugs work?
Atropine like action
= blocks muscarinic ACh receptors = depression in CNS = depresses vestibular reflex centre = alleviates nausea
What type of receptors are H2 receptors?
GPCR - Gs
= increased cAMP & PKA activation
Where are H2 receptors found?
= vascular smooth muscle and parietal (gut) cells
What are H2 anti-histamine drugs used to treat (2)?
Gastric ulcers
Excess acid secretion
What does activation of the H2 histamine receptors cause (6)?
- Vasodilation
- Smooth muscle relaxation
- Gastric acid secretion
- Inhibits antibody synthesis
- Inhibits T cell proliferation
- Inhibits Cytokine producation
Which histamine receptors are involved in gastric acid secretion?
H2
On which cells are the histamine receptors involved in gastric acid secretion located?
Parietal cells
When histamine binds to the H2 receptor on parietal cells what happens that causes gastric acid secretion?
= increased cAMP = activates proton pump = gastric acid secretion
Which two drugs are used to decrease gastric acid secretion?
Cimetidine
Ranitidine
What are the side effects of drugs used to decrease gastric acid secretion?
Diarrhoea
Headaches (imbalance in gastric system)
Dizziness
Skin rashes
Tiredess
n.b. these are pretty minor so they are still commonly used
What is cimetidine used to treat?
Heartburn and peptic ulcers(decrease gastric acid secretion)
What is Ranitidine used to treat?
Peptic ulcers and gastroesophageal reflux disease & urticaria (hives)
What type of receptors are H3 receptors?
GPCR - Gi (inhibits cAMP)
Where are H3 receptors mostly found?
Mostly in the CNS (cortex and sub cortex)
Which channels do the activated G protein interact with?
N-type voltage gated Ca receptors
What happens when the H3 receptor is activated?
- Feedback inhibition of synthesis and release of histamine
- inhibits release of neurotransmitters
What are H3 receptors currently used to research?
sleep disorders, neuropathic pain, obesity, potentially movement disorders. schizophrenia and ADHD
What type of receptors are H4 receptors?
GPCR -> Gi
inhibits cAMP production
Where are H4 receptors found?
Basophils & bone marrow
Thymus
Smooth intestine
Spleen
Colon
What are H4 receptors used for?
Research tool
What happens when H4 receptors are activates?
Regulates neutrophil release from bone marrow
Mediates eosinophil shape change
Mast cell chemotaxis
Beta & Gamma subunits act as PLC (phospholipase C)
What is anaphylaxis?
Whole body reaction of a previously sensitised animal to the sensitising allergen
What are the immediate effects of anaphylaxis?
- smooth muscle contraction
- vasodilation
- increased vascular permeability
- nausea
- abdominal pain
- palpitation
- urticaria (hives)
- hypotension (inadequate circulation) = SHOCK
What is the drug treatment for anaphylaxis?
- immediate adrenaline subcutaneously
- IV maintain volume and supply additional medication
Which other drugs are administered in anaphylaxis?
- H1 receptor antagonists = chlorphenamine & promethazine
- glucocorticoids
What do glucocorticoids do in anaphylaxis?
suppress slow onset urticaria (hives), bronchospasm, laryngeal oedema and hypotension
Which histamine receptor antagonists often have the side effect of sedation?
H1
How do H1 receptor antagonists cause sedation?
They have an atropine like action on ACh receptor = CNS depression = drowsiness (useful for treating terminally ill patients or those experiencing insomnia due to allergic reactions)
Which antihistamines can be used as sedatives for short or long dental procedures?
Diphenhydramine
Hydroxyzine
Promethazine
How long before an appointment are the antihistamines used as sedatives for short or long dental procedures given?
1 hour
Which side effect may H1 antihistamines give?
Anticholinergic effect e.g. dry mouth
How can Gastrooesophageal reflux affect the mouth?
Damage to teeth and buccal mucosa
Glossitis
Burning mouth
Ulceration
What effect can prolonged use of antihistamine syrups have on primary enamel?
Erosive(can be reversed by using fluoride toothpastes)
