Autocoids

Question 1

What are Autocoids?

Answer 1

Autacoids (or “autocoids“)

• Biological factors which act like local hormones, have a brief duration, and act near the site of synthesis.
• Can have many different biological actions including modulation of the activity of smooth muscles, glands, nerves, platelets and other tissues.
• These regulating molecules are also metabolized locally. So the compounds are produced locally, they act locally and are metabolized locally
• Effect of autacoids:
• Primarily localized but large amounts can be produced and moved into circulation, thus resulting in systemic effects

Includes:

• Histamine: (Primary mediator of Allergic reactions)
• Serotonin
• Eicosanids:
  
  • Prostaglandins
  • Leukotrienes

Question 2

Why are Histamine & Serotonin not clinically used?

Instead, what is used?

Answer 2

Because of their broad & undesirable peripheral effects, neither histamine nor serotonin has any clinical applications in the treatment of disease.

However, substances that selectively activate specific receptor subtypes or selectively antagonize the action of these amines are of considerable clinical value

Question 3

Describe the Synthesis of Histamine.

Where does it take place and where is it stored?

What is the Major pathway of degradation?

Answer 3

Synthesis & Storage occur in Mast Cells, Basophils, and Enterochromafin-like (ECL) cells:

[L-Histidine Decarboxylase] (HDC)

• L-Histidine to Histamine + Co2

Degradation: (Major)

[Histamine-N-Methyl Transferase]:

• Histamine to N-Methylhistamine

[N-MethylHistamine Oxidase]:

• N-Methylhistamine to N-Methylimidazole acetic acid

*Little (if any) unmetabolized Histamine is excreted

Question 4

Which factors promote Histamine release?

Which factors inhibit it?

Answer 4

Promote:

• Agn-Ab (IgE) complexes
• Complement proteins
• Inflammation response
• Damaged tissue (burns)
• Medications

Inhibit Histamine Release:

• Epinephrine
• Prostaglandin E2
• Histamine H2

Question 5

Where is H1 receptors located?

What is the net effect of their activation?

Answer 5

H1 receptors: Smooth m., endothelium

Net effects;

• Capillary permeability; Edema
• Vasodilation (via NO) (Rapid); Hypotension & Decreased BP
• Bronchoconstriction (difficulty breathing)
• Intestinal peristalsis; Constipation/Diarrhea
• Pruritis (Itchy skin)
• Pain

Question 6

Where is H2 receptors located?

What is the net effect of their activation?

Answer 6

H2 receptors: Gastric mucosa (Parietal cells), Mast cells, Cardiac muscle

Net effects;

•Increases Acid & Pepsin secretion; Nausea & Heartburn

In CVS:

• Increase HR & Force (Rapid HR)
• Vasodilation (via PKA) (Slower); Decreased BP -> Hypotension
• Mast Cells: Negative feedback on release

Question 7

Where is H3 receptors located?

What is the net effect of their activation?

Answer 7

H3 receptors: Presynaptic autoreceptors & heteroreceptors: Brain, myenteric plexus, other

Net effects;

Decreases release of NTs:

• Histamine
• NE
• ACh
• Serotonin

**H3 Autoceptors: Posterior Hypothalamus

• Feeback inhibition of histamine synthesis & release

H3 Heteroreceptors: Non-histaminergic Neuron

• Inhibit exocytosis of most other NT’s (ACh, GABA, DA, NA, 5HT, etc.)

Question 8

Describe the “Triple Response of Lewis”

Answer 8

“Triple response of Lewis” - Injected intradermally histamine elicits the triple response:

Flush: Erythema - red spot: due to capillary dilatation

Flare: Redness in the surrounding area due to arteriolar dilatation mediated by axon reflex.

Wheal: Raised, swollen area of skin: due to exudation of fluid from capillaries and venules

Question 9

How is exocytosis & degranulation of Mast cells regulated?

Which factors promote it?

Which inhibit it?

Answer 9

Exocytosis is regulated via levels of ATP/cAMP & GTP/cGMP.

Factors promoting exocytosis of histamine increase GTP/cGMP, which activates the appropriate enzymes to induce exocytosis

• (Physical stimuli & Agns, medications, ACh, & anaphylatoxins (complement proteins))

Factors inhibiting exocytosis of histamine increase ATP/cAMP, which inhibits the enzymes necessary for exocytosis

Question 10

Describe the Metabolism of Serotonin (5HT)

Answer 10

[Tryptophan Hydroxylase]

• Tryptophan to 5-Hydroxytryptophan

[Dopa Decarboxylase]:

• 5-Hydroxytryptophan -> 5-Hydroxytryptamine (Serotonin; 5-HT)

[Monoamine Oxidase] (MAO):

• 5-Hydroxytryptamine -> ?

[Aldehyde DH] (AlDH):

• ? -> 5-HIAA
• 5-HIAA is excreted in urine*

Question 11

How are Serotonin receptors important in control of migraines & headaches?

Answer 11

Triptan drugs are agonists at 5-HT 1D and 1B receptors, causing vasoconstriction, thereby reversing the vasodilation causing the headaches

1. Vasoconstriction
2. Inhibition of peptide release
3. Inhibition of Trigeminal neuron activation

Question 12

Describe the origin of Prostaglandins & Leukotrienes.

Describe the beginning steps in their synthesis

Answer 12

Fatty acids (i.e. from the lipid membrane) are converted into Arachadonic Acid (4 double bonds) via [Phospholipase A2]

Arachondic acid is the common origin of both Leukotrienes & Prostaglandins.

Prostaglandins:

[Cyclooxygenase (COX1/COX2)]:

• Arachadonic Acid -> Prostaglandin G2

Leukotrienes:

[5-Lipoxygenase] (5-LOX):

• Arachadonic Acid -> Leukotriene A4

Question 13

What are the effects of Prostaglandins? (General)

Answer 13

Vascular smooth m. (VSM):

Vasodilation or constriction

Non-Vascular smooth m. (NVSM)

Question 14

What are Eicosanoids?

Answer 14

Eicosanoids:

Derived from arachidonic acid and other precursor 20-carbon fatty acids.

The two main groups of eicosanoids are prostaglandins and leukotrienes.

The ratio of omega-6 and omega-3 fatty acids in the diet plays an important role in the activity of eicosanoid end products.