Autacoids and Serotonin

• Autacoids originate from the Greek words "autos" (self) and "acos" (relief).
• Autacoids are local hormones, have short half-lives, and act near their synthesis site.
• They display diverse physiological and pharmacological activities, function at multiple sites and have multiple functions in the body.

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.
• The terms 'Sero' (blood) and 'tonin' (tone) make up 'Serotonin'.
• It was identified in 1951 as a vasoconstrictor.
• Platelets release it to promote local vasoconstriction at the site of clotting.
• Most is stored at enterochromaffin cells, platelets, and in the nervous system.
• In Carcinoid syndrome, Serotonin is overexpressed.
• Serotonin is mostly metabolized by monoamine oxidase (MAO).
• It is a precursor of melatonin.
• Mechanical and neuronal stimuli trigger its release.
• It activates serotonin receptors as its mechanism of action.
  • There are 6 families of G protein-coupled receptors.
  • There is 1 ligand-gated ion channel (5-HT3).
  • There are 15 subtypes (and growing).
  • It is mostly distributed along the CNS, platelets, and smooth muscle.

Serotonin and the Nervous System

• It can be both inhibitory and excitatory, depending on the receptors expressed on the target tissue.
• 5-HT1A is an inhibitory receptor (agonist: repinotan) has antinociceptive action and reverses opioid-induced respiratory depression.
• 5-HT4 is an excitatory receptor (agonist: renzapride) acts as a gastroprokinetic and antiemetic agent, with activity on other receptors.
• Serotonin functions as an antidepressant via SSRIs.
• It controls the vomiting center at the medulla (5-HT3 antagonist: Ondasentron).
• It constricts cerebral blood vessels (Triptans).
• Serotonin stimulates the chemoreceptor reflex through 5-HT3, leading to bradycardia and hypotension.

Serotonin + the Respiratory System

• It has a minimal effect on bronchiolar smooth muscle stimulation (5-HT2A).
• Elevated serotonin levels, such as in Carcinoid Syndrome, may lead to bronchoconstriction.
• It can lead to hyperventilation from the chemoreceptor reflex or activation of bronchial sensory nerve endings.

Serotonin and the Cardiovascular System

• It leads to vascular smooth muscle contraction (5HT2).
• It mainly dilates coronary vessels, but it can constrict coronary arteries with endothelial dysfunction.
• It dilates blood vessels in skeletal muscle.
• It is a vasoconstrictor, except in skeletal muscle and heart.
• It can elicit reflex bradycardia via activation of 5-HT3 receptors on chemoreceptor nerve endings.
• Prolonged elevation can lead to subendocardial fibroplasia, leading to valvular or electrical malfunction.

Serotonin in the GI Tract

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

Pharmacology + Serotonin

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

Serotonin Agonists

• Buspirone (Buspar): a 5-HT1A agonist and nonbenzodiazepine anxiolytic.
• Dexfenfluramine (Redux): a 5-HT2C agonist & appetite suppressant, but was withdrawn due to cardiac valve toxicity.
• Sumatriptan (Imitrex): a 5HT1d/1b agonist used to treat migraine by inhibiting vasodilation and inflammation.
• Fluoxetine (Prozac), Sertraline (Zoloft): indirect-acting, serotonin-selective reuptake inhibitors used for treating depression.
• Trazodone (Desyrel): Metabolized into m-chlorophenylpiperazine, a 5HT1b activator and used to treat depression and insomnia. - Multiple side effects may limit its use.
• Tegaserod (Zelnorm) and Alosetron (Lotronox): 5HT4 agonists used for irritable bowel syndrome and constipation. - Alosetron is restricted to women.

Serotonin Antagonists

• Ondansetron (Zofran): a 5-HT3 antagonist used to treat surgery and cancer chemotherapy-induced nausea.
• Cyproheptadine (Periactin): H1, 5HT1, and 5HT2 antagonist used for carcinoid tumors to limit diarrhea and intestinal spams. - It produces sedation and anticholinergic actions.
• Others: Ketanserin (5-HT2), Ritanserin (5-HT2), Clozapine (5HT2a-c), Risperidone (5HT2a-c).

Antiemetic Agents

• They treat vomiting and nausea, including chemotherapy-induced vomiting.
• Several classes of drugs act as antagonists, including: - 5HT3, H1, Dopamine Receptors. - Cholinoreceptor antagonists. - Cannabinoids, Benzodiazepines. - Neurokinin 1 receptor antagonists.
• Anticholinergic drugs reduce the excitability of labyrinthine receptors at the vomiting center. - They are indicated for motion sickness, but not useful as an antiemetic. - Scopolamine (Trans-Scop) is a preferred agent that has a long duration, produces high incidence of anticholinergic effects. - H1 anti-histaminic drugs work by blocking histamine and cholinergic pathways of the vestibular apparatus. - It is used for motion sickness and vertigo. - Meclizine (Antivert) and cyclizine (Marezine) can be given to pregnant women. - Dimenhydrinate (Dramamine) can produce sedation and dry mouth. - Anti-dopaminergic drugs target dopamine receptors in the CTZ and inhibit peripheral transmission to the vomiting center. - They block alpha-1 adrenergic and cholinergic receptors. - They may cause drowsiness, dry mouth, blurred vision, and extrapyramidal effects. - They are contraindicated in Parkinson’s disease. - Ex: Prochlorperazine (Compazine), promethazine (Phenergan), Droperidol (Inapsine) causes Q-T prolongation & torsade de pointes. - Antiserotonergic Agents: they are useful in the treatment of chemo, post-operative, and post-radiation induced nausea. - 5HT3 receptor antagonists at the CNS and GI tract. - Not useful for motion sickness. - Ex: Ondansetron (Zofran), granisetron (Kytril). - Dolasetron (Anzemet) : prolongs Q-T interval. - Palonosetron: IV, long duration. - Can cause headache and mild constipation. - Synergistic effect when combined with corticosteroids. - Cannabinoids contain THC, the active cannabinoid in marijuana. - They inhibit the vomiting center by stimulating CB1 subtype cannabinoid receptors. - Not a frontline drug, reserved for when other effective drugs have failed. - Ex: Dronabinol (Marinol), Nabilone (Cesamet). - Can cause sedation, tachycardia, hypotension, hallucinations and increased appetite. - Benzodiazepines reduce anticipatory vomiting, like lorazepam, diazepam. - Diazepam is useful for the treatment of vertigo.

Eicosanoids

• Eicosanoids result from the oxygenation of polyunsaturated long-chain fatty acids.
• Includes: Prostaglandins (PGE, PGF), thromboxanes (TXA, TXB), leukotrienes (LTB, LTC), hydroperoxyeicosatetraenoic acid(HPETEs), hydroxyeicosatetraenoic acids (HETEs).
• PGE1: decreases gastric acid and pepsin production and causes vasodilation.
• PGE2: vasodilates, nociceptive sensitization, decrease gastric acid and pepsin production, uterine contraction, thermoregulation.
• PGF2α: bronchoconstriction, uterine contraction, aqueous humor outflow.
• PGI2: inhibits platelet aggregation via endothelium production, decrease gastric acid production, inhibits closure of ductus arteriosus.
• TxA2 causes bronchoconstriction and promote platelet aggregation.

Clinical Pharmacology of Eicosanoids

• Dinoprostone (Cervidil): a PGE2 analogue used to promote abortion or to induce labor, given intravaginally in the 2nd trimester. - Prepares the cervix for induction of labor at term. Short half life; metabolized in lungs. - Side effects: nausea, vomiting.
• Carboprost tromethamine (Hemabate): Given intramuscular for 2nd trimester abortion and controls postpartum hemorrhage.
  • Not common, produces too many side effects: vomiting, diarrhea, bronchoconstriction and cardiovascular collapse.
• Alprostadil (Muse): PGE1, second-line treatment for erectile dysfunction.
• Epoprostenol (Flolan): PGI2 analogue used to treat primary pulmonary hypertension. - Lowers peripheral resistance and blood pressure. - It has a short half-life (3-5 mins) and is given IV. - Side effects include: flushing, headache, hypotension, nausea, and diarrhea. - Iloprost (Ventavis;30 mins); treprostinil (Remodulin;4 hrs).
• Zafirlukast (Accolate) and montelukast (Singulair) are leukotriene receptor inhibitors and potent bronchoconstrictors. - Used prophylactically for mild to moderate asthma. - Expensive, headaches, dry mouth, sleepiness, diarrhea, nausea, and vomiting.
• Zileuton (Zyflo) is a lipoxygenase inhibitor used for asthma, prophylactically for mild to moderate asthma. - It's expensive, requires 4 doses per day, and it produces headache, achiness, nausea, and muscle weakness.

Nitric Oxide

• Is the major bioactive component of the endothelial-derived relaxing factor (EDRF).
• It functions as both an autacoid and a neurotransmitter.
• There are three closely related NO synthase isoenzymes: nNOS (neuronal), iNOS (macrophage), and eNOS (endothelial).

NO Physiology

• Cardiovascular System: Potent vasodilator and inhibits neutrophil adhesion to vascular endothelium and platelet aggregation and adhesion. - Nervous System: Acts as a neurotransmitter by facilitating excitatory neurons involving learning and seizures.
• Peripheral nerves: NANC; involved in the reproductive and GI systems.
• Inflammation: increases COX2 activity, prostaglandin production, and local edema.
• Erection Physiology: Triggered by psychological or tactile stimuli through the erection reflex via parasympathetic nerves.
  • Sympathetic input can inhibit erection, leading to nervousness and agitation.
  • Nitric Oxide release promotes erection through vasodilation, penile engorgement.
  • Ejaculation is controlled by alpha-adrenergic receptors.
  • Sympathetic stimulation promotes ejaculation.

Erectile Dysfunction

• Can be caused by: Antidepressants, antianxiety agents, antipsychotics, antidopaminergics, opioids and anti-hypertensives. - Other causes:Organic nitrates, alcohol, THC/marijuana, anabolic steroids, cimetidine, tobacco, cocaine, and many others.
• Treatment includes: Intra-cavernosal injections include: Papaverine (Pavabid; PDE inhibitor and vasodilator), phentolamine (Regitine; PGE1). - Causes painful. - Apomorphine (Apokyn;D1 and D2 agonist): causes nausea, emesis, dizziness, drowsiness.
• Topical Creams include: Nitroglycerin, Minoxidil (Rogaine), and Papaverine (Pavabid). - Sildenafil (Viagra): NO is released in the corpus cavernosum during sexual stimulation, which leads to cyclic GMP accumulation and penile engorgement. - Cyclic GMP is broken down in the penis by PDE5. - Sildenafil inhibits PDE5, enhancing NO action. - It only works if the penis is stimulated.
  - It has a half-life of 4 hrs. - Side effects: decreased blood pressure, headaches, flushing, GI issues, and color vision problems. - Vardenifil (Levitra) has less side effects. - Tadalafil (Cialis) has a longer half life of 24-36 hours.