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

Local hormones: inflammation and anti-inflammatory agents COPY Flashcards

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
What are the **cardiovascular effects** of stimulation of H1 and H2 receptors?
* **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
What are the non-vascular smooth muscle effects of stimulation of H1 and H2 receptors?
* **Contraction** (H1) * Eg. bronchoconstriction, peristalsis
27
What are the **algesic** effects of stimulation of H1 and H2 receptors?
* Pain * Itching * Sneezing * Caused by stimulation of sensory nerves (H1)
28
What is the effect on gastric acid by stimulation of histamine receptors?
* Increase secretion of gastric acid (H2) * Also increase in associated exocrine secretions due to inc blood flow
29
What are the 2 most important clinical roles of histamine?
* Acute inflammation (H1 effects) * Stimulating gastric acid secretion (H2)
30
What consists of the Triple Response?
* **Reddening** (depends on soluble, chemical mediator) * **Wheal** (depends on soluble, chemical mediator) * **Flare** (depends on nerve supply)
31
What happens when histamine stimulates afferent fibres?
* 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
What is meant by antidromic impulses?
* **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
What is the difference between exudate and transudate?
**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
What effect does prostaglandin E2 (PGE2) have on mucus and acid secretion?
PGE2 -\> * Stimulates mucus secretion as well as carbonate secretion * Inhibits acid secretion This promotes neutralisation of acid
35
H1 antagonists treat acute inflammation. Give examples of 1st generation H1 antagonists
* Mepyramine * Diphenhydramine * Promethazine
36
What is Terfenadine?
* 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
What are therepautic benefits and side effects of H1 antagonists?
* **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
Name some archetypal H2 antagonists
* Cimetidine * Ranitidine
39
What are the thereapeutic benefits and side effects of H2 antagonists?
* **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
Bradykinin is generated as a result of activation of what 3 things?
1. **Hagemann factor** + prod of **plasma kallikrein** 2. Production of **lysyl bradykinin** by **tissue kallikreins** 3. Action of cellular **proteases** in kinin formation
41
What are the 3 related vasodilator peptides (kinins), found in the body?
* Bradykinin * Lysyl bradykinin * Methionlyl-lysyl bradykinin All important mediators of inflammatory repsonses
42
How are kinins formed?
* **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
What are pharmacological effects of bradykinin?
* **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
How is bradykinin metabolised?
By kininases I and II
45
How is 5-HT biosynthesised and metabolised?
46
Where is 5-HT released from?
* 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
What are the inflammatory actions of 5-HT?
* 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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