Autacoids:

Histamine Agonists
→ Autacoids have diverse physiological and pharmacological activities; have brief lifetime and act near their site of synthesis
→ Formed by decarboxylation of L-histidine
→ Exists in bound form in granules of mast cells or basophils and in enterochromaffin-like cells in the fundus of the stomach! release histamine to activate parietal cells
Drug Name Receptor Mechanism Indication/Effects Storage and Release
CVS: Immunologic release: Type I HSN
-Vasodilation with H1 and H2 receptors (flushing) -Ag binds to IgE on mast cells/ basophils! Ca2+ mediated
→ H1 receptors: higher affinity but rapid and short lived; degranulation ! release histamine, ATP and other mediators
-linked to G-proteins stimulation leads to release of NO :vasodilation
-constitutive activity! active even in the absence of histamine (anti-histamines → H2 receptors: develops slowly and is more sustained Chemical/Mechanical release:
are thus inverse agonists) -Amines (morphine and tubocurarine) displace bound histamine from
Heart: heparin complex; no energy required
- H2mediated ↑contractility and ↑conduction velocity -mast cell injury causes degranulation and histamine release
- H1 mediated ↓contractility and ↑capillary permeability! edema Adverse Effects
-Located on postsynaptic membranes in brain -Triple response: intradermal injection causes a localized red
-present in endothelium, smooth mm., nerve endings spot(vasodilation), brighter red flush/flare (stimulation of axon Histamine Toxicity: dose related
Histamine H1 -Gq: ↑PLC ! ↑IP3/DAG!↑Ca2+ reflexes) and a wheal (reflects capacity to cause edema) -Flushing
-Hypotension
GI Tract: H1 mediated contraction -Reflex tachycardia d/t vasodilation
-Located on postsynaptic membranes in brain

H2 -present in gastric mucosa, cardiac muscle cells & immune cells
-Gs!↑Adenylyl cyclase!↑cAMP
Bronchioles: H1 mediated bronchoconstriction
-Headache
-GI upset
-bronchoconstriction
Reduces transmitter release from histaminergic and other neurons
H3 CNS: H1 mediated sensory never stimulation (esp. pain/itching)

-wheals
-Found on leukocytes in the BM and blood
Secretory Tissue: H2 mediated activation of gastric parietal cells! -Urticaria (hives) d/t ↑ capillary permeability
-Chemotactic on eosinophils and mast cells
HCl secretion, pepsin/IF production -Anaphylaxis: txt with Epinephrine
H4 -Role in inflammation and allergies

Clinical Uses: Pulmonary Function Testing! provokes bronchial DO NOT give to asthmatics or patients with PUD/GI bleed
hyperactivity (peptic ulcer)

Autacoids: Histamine Antagonists Anti-histamines

Drug Name Class/Description Mechanism/Effects Uses Adverse Effects
Physiological Antagonist DOC for Anaphylaxis and other
Epinephrine Acts at a separate receptor conditions that involve massive
Actions on smooth mm. cells opposite to histamine histamine release
Cromolyn Mast cell stabilizer Reduce mast cell degranulation via unknown
Asthma [mild asthma; slow action]
Nedocromil (release inhibitor) mechanism (β-2 agonists may have same effect)
• diphenhydramine -Sedation (caution with other drugs that cause sedation!
• dimenhydrinate Chlorpheniramine
Inverse Agonist!↓ constitutive activity contraindicated while operating machinery)
Cyclizine 1st generation alone: motion
• promethazine
Px: motion sickness First Generation H1 Antagonists -Dry mouth d/t anticholinergic effects
Dimenhydrinate sickness and nausea;
Also block cholinergic, α-adrenergic, serotonin -Autonomic blocking actions are additive with those of muscarinic
Diphenhydramine somnifacient! insomnia
Cross the BBB! Sedative effects -M1 and local anesthetic receptor sites (unrelated to antagonists and α-antagonists
Hydroxyzine • M blocker ^like scopolamine
More likely to block autonomic receptors • α blocker their blocking of H1 receptors) -Acute poisoning: common in young children; hallucinations,
Meclizine Allergic conditions:
• 5HT blocker
excitement, ataxia, convulsions; untxted! coma and collapse of
Promethazine • Na channel blocker
-allergies caused by antigens acting
(local anesthetic) cardiorespiratory system
of IgE-antibody sensitized mast
Cardiac toxicity: involves blockade of HERG K+ channels in heart!
cells
prolongation of the action potential by blocking cardiac K+ channels
Second generation H1 Antagonist
Fexofenadine -Astemizole and Terfenadine withdrawn from US! torsades de
DOC in controlling sxs of allergic
Loratadine pointes (potentially fatal)
Less sedating b/c they are less able to cross the BBB !less Inverse Agonist!↓ constitutive activity rhinitis and urticaria
Cetirizine -Combo with ketoconazole, itraconazole, macrolide antibiotics
liposoluble
Astemizole (erythromycin) or grapefruit juice! toxicity by inhibiting CYP3A4!↑
!actively pumped out of brain by P-glycoprotein Ineffective in txt of bronchial
Terfenadine antihistamine concentration in blood
transporter asthma

**Fexofenadine lacks cardiac toxicity effects
Peptic ulcers (promotes healing) -Extremely safe and usually don’t occur: HA, dizzy, diarrhea,
constipation, muscular pain
Competitively and reversible H2 inhibitors! Acute stress ulcers associated with - IV !confusion, hallucination, agitation (more common w/
↓cAMP! ↓ gastric acid secretion induced by major trauma in ICU pts. cimetidine)
Cimetidine
histamine or gastrin NOT secretion induced by - Rapid IV infusion!bradycardia and hypotension (give over 30min)
Antacids Ranitidine
H2 Antagonist muscarinic agonists GERD prevention and txt (may not -blood dyscrasias and reversible liver abnormalities (Rare)
Famotidine
work for at least 45min)
Nizatidine
Can cross placenta but have not shown harmful Cimetidine:
-tidine effects!give only when necessary - inhibits CYP450!slow metabolism of other drugs
-binds to androgen receptors! gynecomastia, ↓sperm count,
galactorrhea
no problems
in pregnancy
 Autacoids: Serotonin Agonists and Antagonists
→ Formed from L-tryptophan via hydroxylation followed by decarboxylation
→ Stored or rapidly inactivated by MAO mediated oxidation
→ Found in enterochromaffin cells in the GI tract, platelets, and raphe nuclei of the brain stem (where the cell bodies of serotonergic neurons are found)
→ Precursor of melatonin in the pineal gland
→ Brain serotonergic neurons involved in mood, sleep, appetite, temperature regulation, perception of pain, blood pressure regulation and vomiting
Drug Name Class/Description Mechanism/Effect Uses Adverse Effects
Seven families of
GI tract:
5-HT receptor
-5-HT2 mediated ↑GI motility & vasoconstriction
subtypes
-5-HT4 mediated ↑ ACh release! mediates

prokinetic effects of serotonin agonists
Serotonin (5-HT) -5-HT3 is the only No clinical applications as a drug overproduction of 5-HT! severe diarrhea
CVS: 5-HT2 mediated constriction of veins/arteries
ligand-gated ion
Platelets: 5-HT2A mediated platelet aggregation
channel, all
CNS: 5-HT3 mediated vomiting reflex and pain/itch
others are G-
perception ^ion channel
protein coupled
on CN5
DOC for acute severe migraines (not Contraindications:
on BV
-Reduce both sensory activation in the periphery prophylaxis) • patients with CAD or angina
5-HT 1D/1B
Sumatriptan and nociceptive transmission in the brainstem - may cause coronary vasospasm
Agonist
(prototype) trigeminal nucleus!diminish central sensitization Migraines are d/t calcitonin gene-related
(Triptans)
-cause vasoconstriction peptide, substance P and neurokinin A!
vasodilation
Prokinetic Agent! promote and organize gut
motility Somnolence, Nervousness, & Dystonic rxns :5HT3R
-facilitates ACh release from enteric neurons Extrapyramidal effects & tardive dyskinesia (Rare) D2R
Galactorrhea (infrequent)
Gastroparesis
Metoclopramide Central anti-dopaminergic actions! antinauseant,
5-HT4 Agonist Emesis
Cisapride antiemetic Cisapride no longer available in US d/t cardiac effects!
D2 antagonist GERD
↑ action potential! QT prolongation! v-tach, v-fib,
Peripheral anti-dopaminergic actions!enhance torsades de pointes (esp. with other drugs that inhibit
prokinetic activity by counteracting the inhibitory CYP3A4)
effect of D2 receptors
Antagonists Allergic/ Vasomotor rhinitis
H1 effect
Allergic conjunctivitis
Potent H1 blocking actions
Cold urticaria

Dermatographism :hives - able to draw on skin
Cyproheptadine 5-HT2 Antagonist Blocks smooth mm. effects of serotonin and
Carcinoid Tumor effects on smooth mm.
H1 antagonist histamine, but has no effect on gastric acid
M antagonist Serotonin Syndrome ( ↑5-HT1A and 5-HT2
secretion
stimulation! hyperthermia, mm. rigidity,
myoclonus! can be fatal)

controls severe nausea and vomiting in
Ondansetron 5-HT3 Antagonist Powerful anti-emetic
patients undergoing chemotherapy

Ergotamine Nausea and vomiting (most common)
Migraine
Dihydroergotamine α receptors
Bromocriptine 5HT receptors Ergotamine and Ergonovine- vasospasm
Agonist, partial agonist, and antagonist actions at Hyperprolactinemia d/t pituitary tumor
Cabergoline - agonist
- partial agonist
α-adrenoceptors and 5-HT receptors
- antagonist Contraindicated in pregnant women, pts with
Ergot Alkaloids Postpartum Hemorrhage when oxytocin is
peripheral vascular disease. CAD, HTN, and impaired
DAgonist or partial agonist action at CNS dopamine
receptors ineffective [IM]
Ergonovine hepatic/renal fxn
receptors
- agonist
Methylergonovine - partial agonist
[IV] Ergonovine: provoke coronary artery
Should not be used concurrently with drugs that cause
spasm! diagnose variant angina
vasoconstriction

coronary aa
look like a vine


Autacoids: Eicosanoids and Eicosanoid Antagonists
→ Subgroups includes prostaglandins, prostacyclins, thromboxanes, and leukotrienes
→ Generated de-novo from arachidonic acid found esterified in phospholipids; not found preformed
→ Direct activation of phospholipase A2 or ↑ Ca2+ can activate eicosanoid synthesis
→ Cyclo-oxygenase pathway: initiates biosynthesis of PGs, Prostacyclins and thromboxanes
o COX1 found in most cells as a constitutive enzyme and the PGs it produces are involved in normal homeostasis
o COX2 found in inflammatory cells and is expressed by growth factors, tumor promoters, and cytokines (LPS endotoxin associated)
→ Lipoxygenase Pathway: initiate the synthesis of leukotrienes and lipoxins via 5-lipoxygenase
o Present in inflammatory cells
o Associated with asthma, anaphylactic shock, and cardiovascular disease
o LTC4 and LTD4! potent bronchoconstriction and are primary components of slow-reacting substance of anaphylaxis (SRS-A) secreted in asthma and anaphylaxis
o LTB4 is a potent neutrophil chemoattractant

Drug Name Class Description MOA Uses

Ripen cervix at or near term ≈induce labor
Dinoprostone PGE2
Abortion

Ripen cervix at or near term ≈induce labor

Postpartum hemorrhage
Misoprostol PGE1 synthetic derivative Abortion when used in combination with a progesterone
antagonist (mifepristone/methotrexate)
Act in autocrine and paracrine fashion
Prevention of peptic ulcers in patients taking ↑doses of NSAIDS

Bind to G-protein coupled receptors (Gs, Gi or Gq)
Carboprost Postpartum hemorrhage
15-methyl-PGF2α
Tromethamine Eicosanoids Abortion
Contractile effects on smooth mm. are mediated by release of
Ca2+ IV!maintain patency of the ductus arteriosus in infants with
transposition of the great vessels
Alprostadil PGE1 Relaxing effects are mediated by elevation in cAMP
Impotence
(vasodilator) Severe pulmonary HTN (↓ peripheral, pulm, and coronary
PGI2
Epoprostenol resistance)
Prostacyclin
Prevents platelet aggregation in dialysis machines
AE:

Latanoprost PGF2α Glaucoma (↑ outflow of aqueous humor) •• conjunctival hyperemia

iris pigmentation
• hypertrichosis

Zileuton Inhibits 5-lypoxygenase Moderate-severe asthma in pts. who are poorly controlled by
Eicosanoid
Zafirlukast Leukotriene inhibitors conventional therapy or experience adverse effects with
Antagonists Inhibits binding of LTD4 to its receptor on target tissues
Montelukast corticoids

Stimulate lipocortin! Inhibit cytosolic phospholipase A2!

block arachidonic acid
Glucocorticoids Anti-inflammatory actions

Inhibit COX-2 synthesis

NSAIDs Inhibit COX 1 and COX 2 Antipyretic, analgesic and anti-inflammatory activity