Pharmacology Flashcards
What does a Gs subunit of a GPCR do?
stimulate adenylate cyclase and increase cAMP production and PKA activation
What does a Gq subunit do?
Stimulate phospholipase C, and increase IP3 and diacylglycerol leads to PKC activation and calcium release from the endoplasmic reticulum.
What does Gi/o subunit do?
inhibit adenylate cyclase, decrease cAMP production, Beta-Gamma subunit inhibits calcium ion channels and activates potassium ion channels.
Examples of ionotropic receptors?
- serotonin= 5-HT3 receptors
- ATP= P2X receptors
- Acetylcholine= nicotinic receptors
What happens when an inflammatory response goes wrong?
- Type I hypersensitivity
- Airway disorders
- autoimmune haemolytic anaemia- dogs
- sweet itch- horses
What are some of the principle mediators of inflammation
Histamine, Bradykinin, nitric oxide, cytokines= interleukins, interferons, chemokines, colony-stimulating factors; Eicosanoids= prostaglandins, thromboxanes, leukotrienes; other plasma proteins= complement, coagulation and fibrinolytic factors; platelet-activating factors, Neuropeptides
What are the main vascular responses to inflammation?
- Vasodilation
- Increased vascular permeability
- Exudation
Where are mast cells produced?
bone marrow, released as immature cells and mature in the tissues.
where are mast cells found?
-beneath the skin, throughout the respiratory system, digestive and urinary tracts
What receptor do mast cells express?
FcεRI with a high affinity to IgE
What are the roles of histamine?
- tissue repair and inflammation
- control of local blood supply- vasodilation and vascular permeability
- contributes to allergic and anaphylactic reactions
- neurotransmitters in the CNS
- Gastric acid secretion
where is histamine found?
- Throughout the body but in high concentrations around the lungs, skin, GIT, and brain= the interfaces between the body and the outer environment.
- Present in mast cells and basophils- that contain granules
- Found in neurones and enterochromaffin-like cells in stomach
What are the steps of Mast cell degranulation?
- Priming of mast cell
- Secondary exposure to the allergen
- Binding of IgE which increases Ca²⁺ concentration in cell
- Migration and fusion of vesicles with cell membrane
- Degranulation
What can inhibit mast cell degranulation?
cAMP
What can cause histamine release?
- neuropeptides
- some basic drugs
How many histamine receptors are there?
4- and they are GPCR
What are the histamine receptors?
- H1
- H2
- H3
- §H4
What does H1 histamine receptor do?
This is the most important in an inflammatory response:
- System vasodilation. ) Increased IP3 and DAG- Stimulate Ca²⁺
- Increased vascular permeability ) ⤴︎
- itching
- bronchoconstriction
- ileum contraction
- effects on neural action potential firing
What does the H2 histamine receptor do?
- Stimulate gastric acid secretion – receptor coupling, increases cAMP
- Relax smooth muscle
- Speed up heart
- inhibit antibody and cytokine production
- inhibit neutrophil activation
What does H3 histamine receptor do?
-Inhibits neurotransmitter release from neurones -> receptor coupling cAMP reduced
What do H4 histamine receptors do?
- Regulates neutrophil release from bone marrow
- mast cell chemotaxis
- receptor coupling reducing cAMP
What are H1 receptor antagonists?
Class of drugs that treat or prevent allergies
orally active and hepatically metabolised
What does a 1st generation H1 receptor antagonist do?
- Able to cross the blood-brain barrier
- 4-6 hours duration, give dose throughout day
What does the 2nd generation H1 receptor antagonist do?
- Can’t cross the blood-brain barrier
- 12-24 hour duration- one tablet lasts for the whole day.
What are eicosanoids?
Eicosanoids are signalling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid. They are generated from phospholipids which are not stored, they are generated on demand. Major involvement in inflammation= pro-inflammatory.
precursors= 20 carbon fatty acids
What are the three types of eicosanoid?
- prostaglandin
- thromboxane
- leukotriene
give some examples of activators for phospholipase A2
- bradykinin
- antibody-antigen bindings on mast cells
- thrombin
- complement C5A
- Cell damage
What does Phospholipase A2 activate?
- Platelet-activating factor
- Arachidonic acid (precursor)
- can produce other precursors- if the diet is particularly Omega 3 fatty acid-rich then a slightly different arachidonic acid is produced- PGE3 and PGI3
What types of Prostaglandins are there?
PGD2, PGE2, PGI2, PGF2𝛼
What is the enzyme responsible for converting A.Acid to PGG2/ PGH2?
Cyclooxygenase
What are the two forms of cyclooxygenase?
COX1= Constitutively expressed by most cells with lots of roles COX2= Not normally present- expression induced by inflammatory factors
Which cells produce leukotrienes?
- Leukocytes
- Lung tissue cells
- Mast cells
- Platelets
What are the receptor classes for leukotrienes?
- BLT for LTB4- activation and targeting of leukocytes and cytokine production
- cystLT for others- important in asthma, bronchoconstriction and vasodilation
What are the main anti-inflammatories?
- NSAIDS
- Glucocorticoids
- H1 receptor antagonists
- Chondroprotective drugs
- immunosuppressants
What hormones does the anterior pituitary release in response to Corticotropin-releasing factor?
Adrenocorticotropic hormone
What gland does the Adrenocorticotropic hormone affect?
the adrenal gland
What does the adrenal gland release?
- mineralocorticoids
- Glucocorticoids- released in a pulsatile fashion and circadian rhythm
What are corticosteroids?
Steroids released by the adrenal gland.
What is the outer layer of the adrenal gland called and what does it release?
Zona Glomerulosa
releases: mineralocorticoids- these regulate water and electrolyte balance
What’s the inner layer of the adrenal gland called? And what does it produce?
Zona fasciculata
Releases: Glucocorticoids
What is the main animal glucocorticoid?
- corticosterone
What is the main human glucocorticoid?
Hydrocortisone
What is the process of glucocorticoid action?
- binds to receptor- in cells cytoplasm (lipid-soluble)
- moves to nucleus
- increases or decreases gene transcription
What metabolic action do glucocorticoids have?
- decrease glucose uptake and utilisation
- Increase gluconeogenesis
- decrease protein synthesis
- increase protein catabolism
- redistribution of fat
- decrease Ca²⁺ absorption from gut
- increase Ca²⁺ excretion form kidney
Why is the adrenal gland so essential?
-loss of corticosteroids leads to muscle weakness, hypotension, hypoglycaemia, and weight loss.
What is Addison’s disease?
loss of functional adrenal gland through chronic inflammation or autoimmune disease.
What is Cushing’s disease?
-excessive corticosteroid
due to prolonged glucocorticoid administration, excessive adrenal gland activity
-Leads to polyuria, polydipsia, breakdown of proteins, coat problems, and redistribution of fat.
What are the injectable forms of Glucocorticoids?
- Methylprednisolone
- Triamcinolone
- Dexamethasone
Clinical uses of glucocorticoids?
- Asthma
- Recurrent airway obstruction
- Eczema, rhinitis, allergic conjunctivitis
- Hypersensitivity states
- Suppress graft reaction
- acute spinal injury
What are chondroprotective drugs?
- used in osteoarthritis and other joint diseases to protect cartilage
- component building blocks of cartilage and lubricants
Examples of chondroprotective drugs
- Pentosan polysulfate sodium
- Hyaluronan
- Polysulfated glycosaminoglycan
- Orgotein
What is a Hyaluronan drug?
= component of synovial fluid and articular cartilage- may improve joint lubrication.
Pentosan polysulfate sodium
= stimulates hyaluronic acid and glycosaminoglycan in damaged joints to decrease cytokine activity
Polysulfated glycosaminoglycan
incorporated into healthy and damaged cartilage, inhibits PGE2 and catabolic enzymes
Orgotein
Water-soluble metalloprotein for arthritis and soft tissue inflammation
NSAIDS
Inhibit COX- reduce prostaglandin and thromboxane synthesis
anti-inflammatory, anti-pyretic and analgesic
some undesirable effects
What are the two iso forms of COX
COX-1 = normal housekeeping role, inhibition may cause GI issues COX-2 = induced by inflammation, inhibition may cause Renal issues
NSAIDs side effects
- renal toxicity
- hepatotoxicity
- haematology and haemostasis
- injury to articular cartilage
What is a Tyrosine kinase receptor?
Found at the plasma membrane with an extracellular ligand-binding domain, transmembrane domain and intracellular.
What are the effects of Tyrosine kinase Receptors?
leads to an inflammatory response, signalling processes, differentiation, regulate proliferation
What are tyrosine kinase receptors activated by?
growth factors, Cytokines and hormones
