Autacoids, Serotonin and other autocoids

Autacoids

• Autacoids come from the Greek words "autos" (self) and "acos" (relief)
• Display diverse physiological and pharmacological activities
• Act like local hormones, act near the site of synthesis, and have a short half-life
• They possess multiple functions and are active in different body sites

Autacoid Diversity

• Serotonin
• Histamine
• Prostaglandins
• Leukotrienes
• Angiotensin
• Substance P
• Vasopressin
• Bradykinin
• Endothelins
• Vasoactive intestinal peptides
• Atrial Natriuretic gene-related peptide
• Neuropeptide Y

Serotonin

• Serotonin is also known as 5-Hydroxytryptamine
• "Sero" means blood, and "tonin" means tone
• Identified as a vasoconstrictor in 1951
• Released by platelets to promote local vasoconstriction at the site of clotting
• Stored mostly at enterochromaffin cells, platelets, and the nervous system
• Overexpressed in carcinoid syndrome
• Mostly metabolized by monoamine oxidase (MAO)
• It is a precursor of melatonin
• Released by mechanical and neuronal stimuli

Serotonin Mechanism of Action

• Activation of Serotonin Receptors
  • Includes 6 families of G protein-coupled receptors
  • Has one ligand-gated ion channel (5-HT3)
  • Includes 15 subtypes, and still growing
  • Mostly distributed along the CNS, platelets, and smooth muscle

Serotonin on the Nervous System

• Can be either inhibitory or excitatory depending on the receptors expressed on the target tissue
  • 5-HT1A is inhibitory (agonist: repinotan): Induces antinociceptive action, counteracting opioid-induced respiratory depression
  • 5-HT4 is excitatory (agonist: renzapride): acts as a gastroprokinetic and antiemetic agent; can also act on other receptors
• Antidepressants work as SSRIs
• Controls the vomiting center in the medulla
  • 5-HT3 antagonist: Ondansetron
• Constricts cerebral blood vessels via Triptans
• Chemoreceptor reflex results in bradycardia and hypotension through 5-HT3

Serotonin on the Respiratory System

• Can have a minimal effect on bronchiolar smooth muscle stimulation (5-HT2A)
• Elevated serotonin levels, like those caused by Carcinoid Syndrome, can lead to bronchoconstriction
• Can lead to hyperventilation due to the chemoreceptor reflex or activate bronchial sensory nerve endings

Serotonin on the Cardiovascular System

• Leads to vascular smooth muscle contraction (5HT2)
• Dilates coronary vessels, but can constrict coronary arteries with endothelial dysfunction
• Dilates blood vessels in skeletal muscle
• Acts as a vasoconstrictor, except in skeletal muscle and the heart
• Can cause prolonged elevation that may lead to subendocardial fibroplasia and resulting valvular or electrical malfunction

Serotonin on the Gastrointestinal Tract

• Stimulant of gastrointestinal smooth muscle
  • Increases tone and facilitates peristalsis via 5-HT2 and 5-HT4
• Overproduction is associated with severe diarrhea

Serotonin Pharmacology

• Serotonin has no clinical application as a drug
• Receptor subtype-selective agonists and antagonists have clinical applications

Serotonin Agonists

• Buspirone (Buspar)
  • A 5-HT1A agonist
  • Nonbenzodiazepine anxiolytic
• Dexfenfluramine (Redux)
  • A 5-HT2c agonist
  • Was used as an appetite suppressant, but it was withdrawn due to cardiac valve toxicity
• Sumatriptan (Imitrex)
  • A 5HT1d/1b agonist
  • Used for migraine treatment as inhibits vasodilation and inflammation
• Fluoxetine (Prozac), Sertraline (Zoloft)
  • Indirectly acting as serotonin-selective reuptake inhibitors
  • Used for depression treatment
• Trazodone (Desyrel)
  • Metabolized into m-chlorophenylpiperazine
  • 5HT1b activator
  • Used for depression and insomnia
  • Has multiple side effects that may limit its use
• Tegaserod (Zelnorm) and Alosetron (Lotronox)
  • 5HT4 agonist
  • Alosetron is restricted to women only, and it is used for irritable bowel syndrome and constipation

Serotonin Antagonists

• Ondansetron (Zofran)
  • A 5-HT3 antagonist
  • Used as a treatment for surgery and cancer chemotherapy-induced nausea
• Cyproheptadine (Periactin)
  • An H₁ and 5HT₁ and 5HT₂ antagonist
  • Can limit diarrhea and intestinal spams associated with carcinoid tumor
  • Produces sedation and anticholinergic actions
• Ketanserin (5-HT2), Ritanserin (5-HT2), Clozapine (5HT2a-c), Risperidone (5HT2a-c)

Antiemetic Agents

• Used for vomiting and nausea treatment
• Also used for chemotherapy-induced emesis
• Several classes of antagonists
  • 5HT3, H1, Dopamine Receptors
  • Cholinoreceptor antagonists
  • Cannabinoids, Benzodiazepines, and Neurokinin 1 receptor antagonists

Anticholinergic Antiemetics

• Reduce the excitability of labyrinthine receptors at the vomiting center
• UsedMotion sickness
• Not useful as an antiemetic
• Scopolamine (Trans-Scop)
  • Is the preferred long duration agent
  • Has a high incidence of anticholinergic effects

H₁ anti-histaminic Antiemetics

• Work through blocking histamine and cholinergic pathways of the vestibular apparatus
• Treats motion sickness and vertigo
• Meclizine (Antivert) and cyclizine (Marezine) can be given to pregnant women
• Dimenhydrinate (Dramamine)
• These can commonly causesedation and dry mouth

Anti-dopaminergic Antiemetics

• Interact with dopamine receptors in the CTZ and inhibit peripheral transmission to the vomiting center
• Blocks alpha-1 adrenergic and cholinergic receptors
• Side effects include drowsiness, dry mouth, blurred vision, and extrapyramidal effects
• Not used in Parkinson's disease due to dopamine blockage
• Prochlorperazine (Compazine) and promethazine (Phenergan)
• Droperidol (Inapsine) use may result in Q-T prolongation and torsade de pointes

Antiserotonergic Agents

• Useful in the management of chemo, post-operative and post-radiation induced nausea
• 5HT3 receptors antagonists at the CNS and Gl tract
• Not useful for motion sickness
• Ondansetron (Zofran) and granisetron (Kytril)
• Dolasetron (Anzemet) may prolong the Q-T interval
• Palonosetron is administered via IV, for long duration
• Side effects can include headache and mild constipation
• Synergistic effect when combined with corticosteroids

Cannabinoids

• THC is the active cannabinoid in marijuana
• Cannabinoids inhibit the vomiting center by stimulating CB₁ subtype cannabinoid receptors
• Not a frontline drug because other more effective drugs are available
• Examples include Dronabinol (Marinol) and Nabilone (Cesamet)
• Adverse effects: sedation, tachycardia, hypotension, hallucinations and increased appetite

Benzodiazepines

• Used to reduce anticipatory vomiting
  • Examples include lorazepam and diazepam
• Diazepam is useful for treating vertigo

Eicosanoids

• Result from the oxygenation of polyunsaturated long-chain fatty acids
• Prostaglandins (PGE, PGF)
• Thromboxanes (TXA, TXB)
• Leukotrienes (LTB, LTC)
• Hydroperoxyeicosatetraenoic acid (HPETEs)
• Hydroxyeicosatetraenoic acids (HETEs)

Effect of Prostaglandins

• PGE1 reduces gastric acid and pepsin production, and causes vasodilation
• PGE2 causes vasodilation, nociceptive sensitization, decreases gastric acid and pepsin production, induces uterine contraction, and mediates thermoregulation
• PGF2α induces bronchoconstriction, uterine contraction, and aqueous humor outflow
• PGI2 inhibits platelet aggregation via endothelium production, reduces gastric acid production, and inhibits closure of ductus arteriosus
• TxA2 is a bronchoconstrictor and promotes platelet aggregation

Clinical Pharmacology of Eicosanoids

• Dinoprostone (Cervidil)
  • A PGE2 analogue is used to promote abortion or to induce labor
    • For abortion it is given intravaginally in the second trimester
    • Used to prepare cervix for induction of labor at term
    • Has a short half-life and is metabolized in lungs
    • Side effects: nausea, vomiting
• Carboprost tromethamine (Hemabate)
  • Given intramuscularly for the second trimester abortion
  • Controls postpartum hemorrhage
  • Side effects, such as vomiting, diarrhea, and bronchoconstriction, are too severe, resulting in cardiovascular collapse
• Alprostadil (Muse)
  • A PGE₁ is second-line treatment for erectile dysfunction
• Epoprostenol (Flolan)
  • PGI₂ analogue, treatment of primary pulmonary hypertension
  • Lowers peripheral resistance and blood pressure
  • Short half life (3-5 mins); given IV
  • Side effects include: flushing, headache, hypotension, nausea and diarrhea
• Iloprost (Ventavis;30 mins), Treprostinil (Remodulin;4 hrs)
  • Used to treat hypertension
• Zafirlukast (Accolate), montelukast (Singulair)
  • Leukotriene receptor inhibitors
  • Potent bronchoconstrictors
  • Used prophylactically for mild to moderate asthma
  • Expensive, side effects include headaches, dry mouth, sleepiness, diarrhea, nausea and vomiting
• Zileuton (Zyflo)
  • Lipoxygenase inhibitor
  • Used prophylactically for mild to moderate asthma.
  • Side effects include expensive, 4 doses per day, headache, achiness, nausea, muscle weakness

Nitric Oxide

• Endothelial-derived relaxing factor (EDRF): NO is the major bioactive component
• Acts as an autacoid and as a neurotransmitter
• Made by three closely related NO synthase isoenzymes: nNOS (neuronal), iNOS (macrophage) and eNOS (endothelial)

NO Physiology

• Cardiovascular System
  • Potent vasodilator
  • Inhibits neutrophil adhesion to vascular endothelium
  • Inhibitor of platelet aggregation and adhesion
• Nervous System
  • Acts as a neurotransmitter
    • Facilitates excitatory neurons involving learning and seizures
    • Works in peripheral nerves: NANC; reproductive and GI system
• Inflammation
  • Increases COX2 activity, prostaglandin production, and local edema

Erection Physiology

• Triggered by psychological or tactile stimuli
  • Erection reflex occurs through parasympathetic nerves
  • Sympathetic input can inhibit erection; nervousness can make erection difficult
• Nitric Oxide release promotes erection
  • Causes vasodilation, penile engorgement
• Ejaculation controlled by alpha-adrenergic receptors
  • Sympathetic stimulation promotes ejaculation

Erectile Dysfunction

• Caused by:
  • Antidepressants
  • Antianxiety agents
  • Antipsychotics
  • Antidopaminergics and Opioids
  • Anti-hypertensives
  • Organic nitrates
  • Alcohol
  • THC/marijuana
  • Anabolic steroids
  • Cimetidine
  • Tobacco
  • Cocaine
  • Many others

Treatment of Erectile Dysfunction

• Intra-cavernosal injections
  • Papaverine (Pavabid; PDE inhibitor and vasodilator)
  • Phentolamine (Regitine; PGE₁)
  • Can be painful
• Apomorphine (Apokyn; D₁ and D₂ agonist)
  • Side effects: Nausea, emesis, dizziness, drowsiness
• Topical Creams
  • Nitroglycerin
  • Minoxidil (Rogaine)
  • Papaverine (Pavabid)

Sildenafil (Viagra)

• NO is released in the corpus cavernosum with sexual stimulation leading to cyclic GMP accumulation and penile engorgement
• Cyclic GMP is broken down in the penis by PDE5
• Sildenafil inhibits PDE5, enhancing NO action
• Sildenafil has no action unless penis is stimulated
• Has a half-life of 4 hours
• Side effects: decreased blood pressure, headaches, flushing, Gl, color vision problems
• Similar drugs
  • Vardenifil (Levitra): Less side effects
  • Tadalafil (Cialis): Longer half life 24-36 hrs