TUT 8 Flashcards
(11 cards)
Describe in detail the complement cascade. Include in your answer the role or function of the main components within the cascade.
Activation of the complement cascade is initiated by substances derived from microorganisms like endotoxins (e.g. LPS).
- C3 is then cleaved to form C3a and C3b.
- C3a stimulates mast cells to release histamine
- C3b attaches to surfaces of microorganisms and opsonises them, also promtes the breakdown of C5 into C5a and C5b
- C5a also stimulates mast cells to release histmaine which results in inflammation while
- C5b together with C6, C7, C8, C9 form a membrane attack complex. Complex forms channels on the outer membrane of bacteria, allowing fluids to enter thus causing it to rupture aka cytolysis.
What is anaphylatoxin?
Anaphylatoxin is a substance that induces rapid degranulation of mast cells which result in histamine release, vasodilation and increased capillary permeability
-Examples would be C3a and C5a
What is an opsonin?
Opsonin is a substane that coats the surfaces of bacteria which then enhances the chances of phagocytosis
-An example would be 3b
What is a chemotaxin?
A chemotaxin is a substance released by injured tissue and WBC at site of inflammation
- This chemical substances stimulates movement of neurophils and other WBC to site of injury
- An example would be c5a
Regarding bradykinin (BK): (a) Describe how bradykinin is generated. (b) Describe the metabolism and inactivation process of bradykinin. (c) What are the pharmacological actions of bradykinin?
a) During inflamamtion, due to increased vascular permeability, hageman factor, prekallikrein and kininogens leak out of blood vessels. Hageman factor (factor XII) is activated by contact with negativelt charged surfaces of bacteria, LPS, collagen, etc. Activation of hageman factor promotoes the conversion of prekallikrein to kallikrein.
KALLIKREIN CAN PROMOTE HMW-kininogen to bradykinin
b) Kiniases- enzymes that rapidly inactivate kinin found in tissues and plasma. Kininase 1 and kininase 2 (ACE) are responsible for metabolism for bradykinin.
- Bradykinin actions are potentiated by ACE inhibitors, because bradykinin causes vasolidation. ACE inhibitor can upregulate bradykinin action since it can further dilate the blood vessels.
- ACE inhibitor blocking breakdown of bradykinin will increase bradykinin level
c)
- potent vasolidlator
- Increased in vascular permeability
- Potent pain producing agent at sensory neurons
- Spasmogenic action on smooth muscle cells including uterine, intestine and bronchioles
What is an ACE inhibitor?
ACE inhibitor is a substance that inhibits the conversion of angiotensin I to angiotensin II by inhibiting the angiotensin converting enyme (LOWERS BP)
Explain how the effects of bradykinin may be potentiated if the person is on an ACE inhibitor?
- Bradykinin is a vasodilator and increases vascular permeability like the ACE inhibitor –> decreases BP
- Combining both an ace inhibitor and bradykinin decreases the amount of blood pressure
Regarding histamine: (a) Describe how histamine is synthesized and stored. (b) How and when is histamine released? (c) Describe the receptors of histamine? (d) Describe the actions of histamine in different human body systems.
a) Histmaine is synthesied from histdine in presence of an enzyme called histidine decarboxylase. Histamine is found in most tissues (At high concnetration in GIT, lungs and skin). Histamne is stored mostly in the mast cells and basophils
b) Histamine is released during allergic/inflmmatory reaction by exocytosis. Also secreted in response to c3a and c5a that react with specific membrane receptors.
c) Receptors of histmaine are G-protein coupled receptors and there are 4 main types
H1: In smooth muscle(contraction of smooth muscle), in cardiovascular (dilation of blood vessels), in CNS (excitatory function of neurotransmitter, stimulates sensory nerve endings –> causes itching )
H2: In GIT (stimulates secretion of gastric acid), In CNS (excitatory function of neurotransmitter)
H3: In CNS: inhibitory (inhibits its own neuronal synthesis and release) via H3 receptor
H4: In CNS: stimulates sensory nerve endings causing itching (H1 and H4)
Antihistamine blocks the binding of histamine to its receptor
-H1 antagonists are used in the treatment of inflammation
d) histamine can impact on
- Smooth muscle via (h1 receptors ) contract smooth muscle of bronchi, bronchioles, ileum, uterus
- Cardiovascular: dilate blood vessels via H1 receptors
- GIT: via H2 receptors; stimulates secretion of gastric acid
- CNS: Neurotransmitter : excitatory via H1 an H2 receptors, inhibitory via H3 receptors. Stimulates sensory nerve endings causing itching (H1 and H4)
How are the series 1, 2 & 3 prostanoids generated & the series 3, 4 & 5 leukotrienes generated?
Series 2 prostanoids formed by arachidonic acid
Arachidonic acid → PGG2 (via COX (cyclooxygenase) 1 & 2)
PGG2 → PGH2 → TXA2, PGI2, PGD2, PGF2a, PGE2
Series 3 prostanoids: formed by eicosapentaenoic acid (EPA)
Same process as above except it produces TXA3, PGI3, PGD3, PGF3a, PGE3
Series 4 leukotrienes
Arachidonic acid → 5-HPETE (5- hydroperoxyeicosatetraenoic acid) via 5-lipoxygenase
5-HPETE → LTA4
LTA4 → LTC4, LTD4, LTE4 & LTB4
Series 5 leukotrienes (formed by eicosapentaenoic acid)
Same process except it produces LTC5, LTD5, LTE5 & LTB5
Describe the main pharmacological action(s) of: TXA2 and PGE2
TXA2: vasoconstriction, thromobotic (promotes aggeregation of platelets), bronchoconstriction
PGE2
- action via EP1 receptors: contract smooth muscle of GIT, contract smooth muscle of bronchi
- action via EP2 receptors: vasodilation, bronchodilation, stimulate fluid secretion of intestines, relax smooth msucle of GIT
- Action via EP3 receptors: contract smooth muscle of intestines, inhbit secretion of gastric acid, increase secretion of gastric mucus (TO PROTECT MUCOSA: CYTOPROTECTIVE), inhibit lipolysis, inhibit release of autonomic neutrotransmitter (NT), stimulate human uterus contraction in pregnant women
Discuss the roles of Thromboxane A2 and Prostaglandin I2 in the body under homeostatic (normal) and inflammatory conditions.
- Under normal conditions Thromboxane A2 works as a vasoconstrictor, bronchoconstrictor and promotes platelet aggregation
- While PGI2 is used as vasodilator as well as inhibitor of platelet aggregation and GI acid secretion
- Under acute inflammatory conditions –> blood vessels and local tissues produce PGI 2, leading to vasodilator
- Under chronic conditions macrophage and monocytes release Thromboxane A2
