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Physiology & Science: Therapeutics > Local hormones: inflammation and anti-inflammatory agents COPY COPY > Flashcards

Local hormones: inflammation and anti-inflammatory agents COPY COPY Flashcards

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1
Q

Inflammation is the body’s defence response to what two main things?

A
  • Invasion - pathogens, allergens
  • Injury - heat, ultraviolet, chemicals

Inflammation is produced by BOTH innate and adaptive immune systems

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2
Q

What are the 5 signs of inflammation?

A
  • Calor - warmth (inc BF)
  • Rubor - redness (inc BF)
  • Dolor - pain (sensitisation/activation of sens nerves)
  • Tumor - swelling (inc post-capillary venule perm)
  • Functio laesa - loss of function (pain/injury)
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3
Q

Inflammation can be acute or chronic, give examples of both of these

A
  • Acute - eg anaphylaxis, sepsis
  • Chronic - eg atherosclerosis
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4
Q

What are the 5 steps of inflammation (5Rs)?

A
  1. Recognition of injurious agent
  2. Recruitment of leukocytes
  3. Removal of the agent
  4. Regulation (control) of response
  5. Resolution (repair)
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5
Q

Upon injury, what are the microvascular events and how long do they last?

A
  • 1-24 hr
  • Influx of immune cells to area requiring ‘defence’
  • Increased flow in arterioles (histamine, prostaglandins)
  • Capillary bed enlarges + leaks
  • Disruption of venule endothelium increases permeability (histamine, bradykinin)
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6
Q

What are the causes of acute inflammation?

A
  • Trauma (blunt + penetrating)
  • Infection (parasites, bacteria, virus, fungi)
  • Tissue necrosis - ischaemia
  • Foreign bodies (splinters, sutures, dirt)
  • Immune reactions - autoimmune rxns, allergies
  • Physical + chemical agents
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7
Q

What are key properties of local hormones (AKA autcaoids)?

A
  • Produced in response to a wide range of stimuli
  • Synthesised or released only as + when required
  • Local release for local action
  • Inactivated locally to minimise systemic effects
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8
Q

What are examples of local hormones?

A
  • Gastrin
  • CCK
  • Glucagon
  • VIP
  • Sub P
  • Motilin
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9
Q

What are the 3 stages of basic chemical signalling + where do these sometimes occur?

A
  1. Reception
  2. Transduction
  3. Response

Sometimes the response is localised to the cytoplasm, other times in can lead to changes in gene expression within the nucleus itself.

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10
Q

How is histamine synthesised?

A

Synthesised from amino acid histidine by histidine decarboxylase

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11
Q

How is histamine metabolised?

A

Metabolised by imidazole-N-methyltransferase (INMT) and diamine oxidase

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12
Q

Histamine is pre-made, ‘ready to go’ in secretory granules composed of heparin and acidic proteins. Which cells is histamine synthesised, stored and released from?

A
  • Mast cells
  • Basophils
  • Neurones in brian
  • Histaminergic cells in gut (ECL)
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13
Q

What stimulates histamine release?

A

Mast cells express receptors for IgE, C3a & C5a (complement agents) on cell surface - so these stimulate histamine release.

Also insect stings, trauma etc. - all through a rise in intracellular Ca2+

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14
Q

What is release of histamine inhibited by?

A

Inhibited by sitmulation of B-adrenoreceptors

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15
Q

Mast cells are recognised regulators of many tissue functions, such as?

A
  • Blood coagulation, flow + vascular permeability
  • Smooth muscle contraction (peristalsis, bronchoconstriction)
  • Wound healing + fibrosis
  • Regulation of innate + adaptive immune responses
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16
Q

What are the 4 types of histamine receptors?

A
  • H1
  • H2
  • H3
  • H4
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17
Q

Histamine receptors are all G-protein coupled receptors which produce physiological effects by activating secondary messenger systems. What is the location and coupling of H1?

A

H1

  • Gq / PLC, PIP2 -> DAG + IP3
  • Smooth muscle, endothelium, CNS
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18
Q

What is the location and coupling of H2?

A

H2

  • Gs / AC, generation of cAMP
  • Stimulation of PKA
  • Parietal cells -> inc gastric acid secretion
  • Heart -> promotes contraction of heart
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19
Q

What is the location and coupling of H3?

A

H3

  • Gi
  • Decrease in cAMP
  • Neuronal presynaptic terminals
20
Q

What is the location and coupling of H4?

A

H4

  • Gi
  • Decrease in cAMP
  • Basophils
  • Bone marrow
  • Gut
21
Q

Stimulation of which of the histamine receptors produces many of the actions of histamine-mediated inflammation?

A

H1 and H2

Therefore H1 and H2 antagonists are clinically important

22
Q

Senistization of mast cells includes priming and synthesis of IgE. How does priming of mast cells occur?

A

Via IL-4 from Basophils and Th2 cells

23
Q

Which cell synthesises IgE?

A

B cells (regulated by IL-4 and IL-13 from the basophils + Th2 cells)

24
Q

Following sensitisation, allergens can cross-link + bind to IgE on mast cells to stimulate an early and late phase/chornic reaction. What do the early and late reactions consist of?

A
  • Occurs through release of histamines, interleukins, prostaglandins and proteases from the mast cells
  • Early rxn = wheal + flare
  • Late reaction:
    • Smooth muscle -> bronchoconstriction + hyperperistalsis
    • Nerve cell -> pain + itch
25
Q

What are the cardiovascular effects of stimulation of H1 and H2 receptors?

A
  • Dilates arterioles -> ↓ TPR (H1)
  • Inc permeability of post-capillary venules -> ↓ BV (H1)
  • Inc heart rate (H2) - in vivo reflex to try to retain BP to normal
  • Generally involved in ↓BP (↓vascular resistance)
26
Q

What are the non-vascular smooth muscle effects of stimulation of H1 and H2 receptors?

A
  • Contraction (H1)
  • Eg. bronchoconstriction, peristalsis
27
Q

What are the algesic effects of stimulation of H1 and H2 receptors?

A
  • Pain
  • Itching
  • Sneezing
  • Caused by stimulation of sensory nerves (H1)
28
Q

What is the effect on gastric acid by stimulation of histamine receptors?

A
  • Increase secretion of gastric acid (H2)
  • Also increase in associated exocrine secretions due to inc blood flow
29
Q

What are the 2 most important clinical roles of histamine?

A
  • Acute inflammation (H1 effects)
  • Stimulating gastric acid secretion (H2)
30
Q

What consists of the Triple Response?

A
  • Reddening (depends on soluble, chemical mediator)
  • Wheal (depends on soluble, chemical mediator)
  • Flare (depends on nerve supply)
31
Q

What happens when histamine stimulates afferent fibres?

A
  • Known to stimulate axon reflex
  • Orthodromically (normally) stimulates nerve impulse
  • Travels down spinal cord + dorsal root ganglia
  • Passes antidromically down other branches of sensory nerves
  • These antidromic impulses release nerve impulses
  • -> vasodilation (flare, reddening) distant from site of irritation
32
Q

What is meant by antidromic impulses?

A
  • Antidromic impulses refers to impulse conduction along nerve fibre in a direction that is opposite to the normal direction
  • Normal direction known as orthodromic
  • Antidromic impulses release neuropeptides which cause vasodilation distant from site of infection -> third phase of inflammation (flare)
33
Q

What is the difference between exudate and transudate?

A

Transudate is just fluid pushed through the capillary due to high pressure within the capillary. Exudate is fluid and proteins that leak around the cells of the capillaries caused by inflammation.

34
Q

What effect does prostaglandin E2 (PGE2) have on mucus and acid secretion?

A

PGE2 ->

  • Stimulates mucus secretion as well as carbonate secretion
  • Inhibits acid secretion

This promotes neutralisation of acid

35
Q

H1 antagonists treat acute inflammation. Give examples of 1st generation H1 antagonists

A
  • Mepyramine
  • Diphenhydramine
  • Promethazine
36
Q

What is Terfenadine?

A
  • 2nd/3rd gen H1 antagonist
  • Pro-drug
  • Potential cardiac arrythmia actions in high conc
  • Above actions increased by grapefruit juice
  • Grapefruit juice inhibits P450-mediated drug metabolism in liver
  • Fexofenadine = active, non-toxic metabolite of terfenadine
37
Q

What are therepautic benefits and side effects of H1 antagonists?

A
  • Reduce minor inflammatory rxns (eg insect bites, hayfever) but NO significant value in asthma
  • 1st gen drugs = sedative so drowsiness a side effect but sometimes thereapeutic
  • Some (eg. promethazine) are anti-emetic - ‘motion sickness’
  • Anti-muscarainic actions (common in 1st gen drugs) - eg. atropine-like effects of blurred vision, constipation etc.
38
Q

Name some archetypal H2 antagonists

A
  • Cimetidine
  • Ranitidine
39
Q

What are the thereapeutic benefits and side effects of H2 antagonists?

A
  • Reduce gastric acid secretion - for duodenal/gastric ulcers
  • For Zollinger-Ellison syndrome (duodenum + pancreatic tumours inc gastrin secretion)
  • Increase INMT activity so more rapid breakdown of histamine
  • Mental confusion, dizziness, tiredness + diarrhoea sometimes as side effects
  • Cimetidine decreases cytochrome P450 activity so ADR potential + also get gynecomastia
40
Q

Bradykinin is generated as a result of activation of what 3 things?

A
  1. Hagemann factor + prod of plasma kallikrein
  2. Production of lysyl bradykinin by tissue kallikreins
  3. Action of cellular proteases in kinin formation
41
Q

What are the 3 related vasodilator peptides (kinins), found in the body?

A
  • Bradykinin
  • Lysyl bradykinin
  • Methionlyl-lysyl bradykinin

All important mediators of inflammatory repsonses

42
Q

How are kinins formed?

A
  • Kinins are liberated from precursor molecules called kininogens
  • Kininogens - eg. a2 globulins; hmwk; lmwk; t kininogen
  • Kininogens made by hepatocytes
  • Kininogens -> kinins are done by proteases called kallikreins
  • Kinins are then inactivated by kininases
43
Q

What are pharmacological effects of bradykinin?

A
  • Potent vasoactive peptide
  • Increase vascular permeability
  • Vasodilation (decrease BP)
  • Pain
  • Contraction of visceral smooth muscle (gut + bronchus)
  • Stimulation of arachidonic acid metabolism
  • Chemotactic to leukocytes
  • Dry cough
44
Q

How is bradykinin metabolised?

A

By kininases I and II

45
Q

How is 5-HT biosynthesised and metabolised?

A
46
Q

Where is 5-HT released from?

A
  • Platelets release 5HT (+ TXA2) -> platelet aggregation
  • Mucosal EC cells of GI tract -> mediate gut movement + diarrhoea
  • Brain -> cognition, aggression, mating, feeding, sleep, pain, vom
  • Some tumours secrete XS 5HT -> inc proliferation + cell survival
47
Q

What are the inflammatory actions of 5-HT?

A
  • Promotes inflammation by inc number of mast cells at site of tissue injury
  • Stimulates mast cell adhesion + migration
  • Enhances inflammatory rxns of skin, lungs + gut
  • Synergise w/ TXA2 to stimulate platelet activity + vasoconstriction
    • Acivation of TXA2 receptors -> inc 5HT mediated response in blood vessels - Basically, injured arteries + arterioles constrict due to release of 5HT from platelets which plugs the injured site

Physiology & Science: Therapeutics (6 decks)

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