Autacoids

Question 1

What are autacoids?

Examples?

Answer 1

1. Endogenous substances that mediate inflammation

2. Histamine, Serotonin, Lipid-derived eicosanoids, bradykinin, cytokines

Question 2

Histamine-general

Answer 2

z Stored in mast cells and basophils, released by antigen binding to IgE antibodies on cell surface

z Produces vasodilation, flushing, vascular permeability, bronchoconstriction, pain, and itch

Question 3

serotonin-general

Answer 3

Main role in inflammation is vasodilation, but can produce vasoconstriction and platelet
aggregation if tissue is damaged

Question 4

Lipid-derived eicosanoids: prostaglandins, leukotrienes

-general

Answer 4

Modulate pain, bronchial tone, vascular tone, platelet function, inflammatory cell function,
uterine tone, GI function, renal function, CNS function

Question 5

Bradykinin and related peptides

general

Answer 5

Produce pain, vasodilation, vascular permeability, stimulate prostaglandin biosynthesis

Question 6

1. Synthesis of Histamine

2. metabolism of histamine

Answer 6

1. Biosynthesized from histidine via histidine decarboxylase
2. metabolized by:
   - Diamine oxidase (phase I)
   - Histamine-N-methyltransferase (phase II)

Question 7

Storage of histamine

Answer 7

z Mast cells (tissues, especially skin, lung mucosa, intestinal mucosa)

z Basophils (blood)

z Enterochromaffin-like cells in stomach

z Neurons

Question 8

Histamine Receptors

Answer 8

G protein-coupled Receptors:

1. H 1 : peripheral nerve endings, CNS, smooth muscle of blood vessels, bronchi, and intestine; G q -coupled
   - #1 most important is breathing
2. H 2 : gastric mucosa, heart, mast cells, CNS; G s -coupled
   - I have to go #2=stomach
   - Gs b/c s is for sh*t
3. H 3 : autoreceptors on histaminergic neurons in CNS and PNS; G i -coupled
4. H 4 : Eosinophils, neutrophils, CD4 T-cells; G i -coupled
   - H4=CD4

Question 9

What causes histamine release?

Answer 9

1) mast cells and basophils degranulate if surface IgE bind w/antigen
2. Substances released during IgG/IgM rxns that activate complement cascade

3. Certain drugs: benzylisoquinoline, NMJ blockers, opioids, succinylcholine)
   - thus these drugs can cause itchiness

neutrophils, basophils, and others are attarcted to histamine

Question 10

Ways to antagonize histamine

Answer 10

1. Physiological antagonism
   - Example: epinephrine to reverse effects of anaphylaxis
2. Inhibit histamine release
   - Cromolyn sodium
   - Nedocromil
   - above drugs used for asthma
3. Histamine receptor antagonists
   - many are inverse agonists

Question 11

Histamine H1 Receptor effects

Answer 11

1) Vasodilation of small blood vessels
- Most important vascular effect in humans
- Flushing
- Decreased total peripheral resistance
- Decreased blood pressure

2) Increased capillary permeability → edema, urticaria
3) Bronchoconstriction and bronchospasm
4) Nerve endings: pain and itch
5) Contraction of intestinal smooth muscle

Question 12

H1 Antagonists

1. Indications
2. 1st vs. 2nd generation

Answer 12

Introduced in the 1940s and today are among the most
widely used drugs

H1=I PUMA 
1. Indications: 
 z Allergic conditions
 z Urticaria
 z Insomnia
 z Motion sickness
 z Parkinsonian syndrome 

a) 1st generation-more sedation

b) 2nd-less likely to cause drowsiness
* **Low CNS accumulation; effluxed from the CNS via the P-glycoprotein pump system

Question 13

H1 antagonist drugs

Answer 13

1. Diphenyhydramine (Benadryl, Sominex)-1st
2. Certirizine (Zyrtec)-2nd
3. Fexofenadine (Allegra)-2nd
   - active metabolite: terfenadine
4. Loratidine (Claritin, Tavist ND)-2nd
   - active metabolite: desloratidine (clarinex)

Question 14

H1 antagonist Drugs:

Shared general mechanism

Answer 14

All the ones we are studying are INVERSE agonists!

H 1 receptor inverse agonist, stabilizes the inactive conformation of H 1 receptors; blocks the effects of histamine on H 1 receptors in the GI tract, uterus, large blood vessels, and bronchial muscle and suppresses the formation of edema, flare, and pruritus

Question 15

H1 antagonist Drugs:

Shared TX

Answer 15

TX for allergic rhinitis, sneezing, itching, urticaria

***1st generation (diphenyhydramine) add TX for motion sickness, insomnia

Question 16

Histamine H2 Receptor Effects

Answer 16

1)Vasodilation of small blood vessels
2) Increased heart rate: reflex tachycardia and direct
stimulation
-tachycardia due to baroreceptor reflex to vasodialtion

3) Gastric acid secretion due to activation of PARIETAL cell H2 receptor activation

Question 17

H2 Receptor Antagonists and gastric acid

Answer 17

Drug: Cimetidine (Tagamet)
Mechanism: inverse agonist, reduces constitutive activation of H 2 receptors on parietal cells

• 1970s to treat peptic ulcer disease

-Not as efficacious as proton pump inhibitors but cheap,
very safe, and available OTC
** Get 60-70% decrease in 24 hr acid secretion

• Especially effective at inhibiting nocturnal acid secretion, but less effective on meal-stimulated acid secretion

Question 18

Serotonin

1. Synthesis
2. Storage
3. Receptors

Answer 18

1. Biosynthesized from tryptophan
2. Storage sites:
   a)Most 5-HT in the body is in enterochromaffin cells in GI
   epithelium

b) In blood, 5-HT is stored in platelet vesicles
- platelet aggregation and activation

b) In brain, 5-HT is in synaptic vesicles
- sex, temp, mood, sensory, appetite

3. At least 14 receptor subtypes:
   a) Most are G protein-coupled
   - mostly Gq
   b) One, the 5-HT 3 receptor, is a ligand-gated ion channel

Question 19

Serotonin Synthesis and metabolism

Answer 19

1. Synthesis:
   a) tryptophan + ttryptophan hydroxylase (TPH) = 5HTP
   b) 5HTP + Aromatic Amino Acid decarboxylase (AAAD) = SEROTONIN!!!
2. metabolism
   a) melatonin!!! Formed from 2 Phase 2 enzymes: Arylalkylamine-N-acetyltransferase (AANAT) + ASMT

Question 20

Some Effects of 5HT

Answer 20

1. CNS neurotransmitter
   a) Serotonin receptors in the CNS affect mood, appetite, sexual activity, thermoregulation, sensory perception, sleep, memory,
   cognition
   b) Mediates vomiting in the chemoreceptor trigger zone (5-HT 3 receptors)
2. GI tract
   a) 5-HT 3 activation suppresses GI motility
   b) 5-HT 4 activation promotes motility (“4 let it Pour”
3. CV system
   a) Released from platelets to initiate blood clotting
   b) Vasoconstriction (5-HT 1 , 5-HT 2 , 5-HT 7 )
   • **Blood pressure
   • **Migraine

Question 21

Migraines and 5HT

Answer 21

1) Pathophysiology likely involves neurogenic origin followed by
vasodilation

2) 5-HT is a key mediator of migraine pathogenesis
* **Plasma and platelet 5-HT concentrations vary with the different phases of a migraine episode
* **Urine concentrations of 5-HT and its metabolites are elevated during most migraine attacks
* **Agents that release 5-HT from intracellular stores precipitate migraine

Drugs: Ergotamine (partially both) and Sumatriptan (agonist)

Ergotamine also used to induce labor and for vasoconstriction post partum

Question 22

Ergotism

Answer 22

From Ergotamine (Ergomar):

angina, asthenia, coronary vasospasm, cramps, myalgia,
paresthesias, changes in HR; vasoconstriction may result in hypothermia or tissue necrosis

Question 23

Serotonin Receptor Migraine Drugs: General Precautions

Answer 23

CV: angina, arteriosclerosis, coronary artery disease, hypertension, peripheral
vascular disease, Raynaud’s disease, thrombophlebitis, MI, stroke

Hepatic disease

Renal insufficiency

Question 24

Migraines and…

1. various anti-seizure drugs (valproic acid)
2. Feverfew (Tanacetum parthenium, Migraban)

Answer 24

Both prophylactic for migraines

1. questionable
2. also has antiinflammatory effects; prevents release of 5HT, inhibits vasospasm

Question 25

Serotonin Syndrome

Answer 25

1) Serotonin syndrome is caused by excessive serotonin concentrations at its receptors 2) Can be precipitated by the concomitant use of drugs (SSRIs, MDMA-ecstasy) that enhance synaptic serotonin concentrations, usually developing in less than 12 hr ``` 3)Symptoms z Agitation z Hyperthermia z Flushing z GI disturbances z Myoclonus z Rhabdomyolysis z Tremor and seizures ``` See slide 34

Question 26

Management of Serotonin Syndrome

Answer 26

*Remove precipitating drugs *Supportive care z Monitor vital signs z IV fluids *Control agitation z Benzodiazepines-anti-seizure and for anxiety so helps calm patient and treat myoclonus *Antagonize 5-HT actions z Cyproheptadine: H 1 , 5-HT 2, D 3 , M 1-5 blocker ``` *Control hypertension and tachycardia z Sodium nitroprusside (NO brings down BP right away) z Esmolol (IV Beta-1 receptor blocker to reduce tachycardia ) ``` *Control hyperthermia z Vecuronium-NMJ blocker to reduce heat produced by the monoclonus z No role for antipyretic agents