Autacoids Flashcards
What are autacoids?
Examples?
- Endogenous substances that mediate inflammation
2. Histamine, Serotonin, Lipid-derived eicosanoids, bradykinin, cytokines
Histamine-general
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
serotonin-general
Main role in inflammation is vasodilation, but can produce vasoconstriction and platelet
aggregation if tissue is damaged
Lipid-derived eicosanoids: prostaglandins, leukotrienes
-general
Modulate pain, bronchial tone, vascular tone, platelet function, inflammatory cell function,
uterine tone, GI function, renal function, CNS function
Bradykinin and related peptides
general
Produce pain, vasodilation, vascular permeability, stimulate prostaglandin biosynthesis
- Synthesis of Histamine
2. metabolism of histamine
- Biosynthesized from histidine via histidine decarboxylase
- metabolized by:
- Diamine oxidase (phase I)
- Histamine-N-methyltransferase (phase II)
Storage of histamine
z Mast cells (tissues, especially skin, lung mucosa, intestinal mucosa)
z Basophils (blood)
z Enterochromaffin-like cells in stomach
z Neurons
Histamine Receptors
G protein-coupled Receptors:
- H 1 : peripheral nerve endings, CNS, smooth muscle of blood vessels, bronchi, and intestine; G q -coupled
- #1 most important is breathing - 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 - H 3 : autoreceptors on histaminergic neurons in CNS and PNS; G i -coupled
- H 4 : Eosinophils, neutrophils, CD4 T-cells; G i -coupled
- H4=CD4
What causes histamine release?
1) mast cells and basophils degranulate if surface IgE bind w/antigen
2. Substances released during IgG/IgM rxns that activate complement cascade
- Certain drugs: benzylisoquinoline, NMJ blockers, opioids, succinylcholine)
- thus these drugs can cause itchiness
neutrophils, basophils, and others are attarcted to histamine
Ways to antagonize histamine
- Physiological antagonism
- Example: epinephrine to reverse effects of anaphylaxis - Inhibit histamine release
- Cromolyn sodium
- Nedocromil
- above drugs used for asthma - Histamine receptor antagonists
- many are inverse agonists
Histamine H1 Receptor effects
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
H1 Antagonists
- Indications
- 1st vs. 2nd generation
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
H1 antagonist drugs
- Diphenyhydramine (Benadryl, Sominex)-1st
- Certirizine (Zyrtec)-2nd
- Fexofenadine (Allegra)-2nd
- active metabolite: terfenadine - Loratidine (Claritin, Tavist ND)-2nd
- active metabolite: desloratidine (clarinex)
H1 antagonist Drugs:
Shared general mechanism
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
H1 antagonist Drugs:
Shared TX
TX for allergic rhinitis, sneezing, itching, urticaria
***1st generation (diphenyhydramine) add TX for motion sickness, insomnia
Histamine H2 Receptor Effects
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
H2 Receptor Antagonists and gastric acid
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
Serotonin
- Synthesis
- Storage
- Receptors
- Biosynthesized from tryptophan
- 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
- 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
Serotonin Synthesis and metabolism
- Synthesis:
a) tryptophan + ttryptophan hydroxylase (TPH) = 5HTP
b) 5HTP + Aromatic Amino Acid decarboxylase (AAAD) = SEROTONIN!!! - metabolism
a) melatonin!!! Formed from 2 Phase 2 enzymes: Arylalkylamine-N-acetyltransferase (AANAT) + ASMT
Some Effects of 5HT
- 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) - GI tract
a) 5-HT 3 activation suppresses GI motility
b) 5-HT 4 activation promotes motility (“4 let it Pour” - CV system
a) Released from platelets to initiate blood clotting
b) Vasoconstriction (5-HT 1 , 5-HT 2 , 5-HT 7 )- **Blood pressure
- **Migraine
Migraines and 5HT
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
Ergotism
From Ergotamine (Ergomar):
angina, asthenia, coronary vasospasm, cramps, myalgia,
paresthesias, changes in HR; vasoconstriction may result in hypothermia or tissue necrosis
Serotonin Receptor Migraine Drugs: General Precautions
CV: angina, arteriosclerosis, coronary artery disease, hypertension, peripheral
vascular disease, Raynaud’s disease, thrombophlebitis, MI, stroke
Hepatic disease
Renal insufficiency
Migraines and…
- various anti-seizure drugs (valproic acid)
- Feverfew (Tanacetum parthenium, Migraban)
Both prophylactic for migraines
- questionable
- also has antiinflammatory effects; prevents release of 5HT, inhibits vasospasm
Serotonin Syndrome
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
Management of Serotonin Syndrome
*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
