Autacoids, Histamine, Serotonin, Ergot Alkaloids, Vasoactive Peptides, and Nitric Oxide

Learning Objectives

• Classify the following drug groups under autacoids/anti-autacoids:

  • Histamine receptor antagonists.

  • Serotonin receptor agonists and antagonists.

  • Ergot alkaloids.

  • Vasoactive peptides and antagonists.

  • Eicosanoids and antagonists.

  • Nitric oxide.

• Discuss the pharmacologic properties of the drug groups mentioned.

• Apply/choose the appropriate drug under autacoids given a particular case.

I. Autacoids

• Definition

  • Ethymology: Derived from the Greek words "αὐτός" (self) and "ἄκος" (cure).

  • Autacoids are endogenous molecules featuring complex physiologic and pathophysiologic functions.

  • They exert potent pharmacological effects when administered as exogenous drugs.

• The Four Autacoid Groups

  • Amines (Protein): Includes Histamine and Serotonin ($5-hydroxytryptamine$ or $5-HT$).

  • Vasoactive Peptides (Protein): Includes both Vasoconstrictors and Vasodilators.

  • Eicosanoids (Derived from fatty acids): Includes Prostacyclin, Prostaglandin $E$, Prostaglandin $F$, Thromboxanes, and Leukotrienes.

  • Nitric Oxide: A gaseous signaling molecule.

• Overview and Clinical Status

  • Tegaserod: Initially withdrawn due to cardiotoxicity. Reintroduced in $2019$, then withdrawn again in $2022$ due to business decisions.

  • Prucalopride is identified as a superior example for $5-HT_4$ partial agonists as it is available in the US market.

II. Histamine

• Synthesis, Storage, and Metabolism

  • Synthesis: Histamine is synthesized via the decarboxylation of the amino acid $L-histidine$.

  • Metabolism: Metabolized by amine oxidases, specifically Monoamine Oxidase (MAO) and Diamine Oxidase (DAO). The major metabolite is Imidazole Acetic Acid (IAA), which can be detected in urine to suspect systemic disease involving excess histamine production.

  • Storage Locations:

    1. Mast Cells and Basophils: Stored in granules. Concentrated at sites of potential tissue injury such as the nose, mouth, feet, internal body surfaces, and blood vessels. Histamine here acts as an important mediator of immediate allergic and inflammatory reactions.

    2. Enterochromaffin-like (ECL) Cells: Located in the stomach. Responsible for activating gastric-acid producing parietal cells.

    3. Brain: Acts as a neurotransmitter for neuroendocrine control, body weight regulation, and sleep/arousal cycles.

• Physiological Effects

  • Triple Response: Observed after intradermal injection of histamine, consisting of a Red spot + Edema + Flare response.

  • Dose-Related Adverse Effects (Large Doses): Flushing, urticaria, hypotension, tachycardia, headache, bronchoconstriction, and GI upset.

  • Scombroid Fish Poisoning: Occurs when consuming spoiled fish containing large amounts of histamine produced by bacteria on the flesh.

  • Clinical Application: Histamine itself has no clinical application; pharmacological utility lies in blocking histamine receptors.

• Histamine Receptor Subtypes

  • $H_1$ Receptor: Distributed in smooth muscle, endothelium, and brain.

    • Mechanism: Gq protein coupling, activating $IP_3$ and DAG.

    • Action: Vasodilation.

    • Selective Agonists: Histaprodifen.

    • Selective Antagonists: Mepyramine, Tripolidine, Cetirizine ($2^{nd}$ generation), and Diphenhydramine ($1^{st}$ generation).

  • $H_2$ Receptor: Distributed in gastric mucosa, cardiac muscle, mast cells, and brain.

    • Mechanism: Gs protein coupling, increasing cAMP levels.

    • Action: Acid secretion. By blocking $H_2$, gastric acid secretion decreases.

    • Selective Agonists: Amthamine.

    • Selective Antagonists: Cimetidine, Ranitidine, Famotidine, Tiotidine.

  • $H_3$ Receptor: Presynaptic receptors and heteroreceptors found in the brain, myenteric plexus, and other neurons.

    • Mechanism: Gi protein coupling, which is inhibitory (decreases cAMP).

    • Selective Agonists: $R-α-Methylhistamine$, Imetit, Immepip.

    • Selective Antagonists/Inverse Agonists: Thioperamide, Iodophenpropit, Clobenpropit, Tiprolistan (Pitolisant), Proxygan.

    • Pitolisant MOA: An inverse agonist that reduces inhibitory activity, thereby stimulating wakefulness in narcolepsy.

  • $H_4$ Receptor: Found in eosinophils, neutrophils, mast cells, and CD4 T cells.

    • Mechanism: Gi protein coupling (inhibitory).

    • Selective Agonists: Clobenpropit, Imetit, Clozapine.

    • Toxicity: Clozapine stimulation of $H_4$ inhibitory activity can lead to agranulocytosis (inhibiting production of granulocytes).

    • Selective Antagonists: Thioperamide.

III. Histamine Antagonists

• General Categories

  • Physiologic Antagonist: Epinephrine is used for anaphylaxis, acting on adrenergic receptors to oppose histamine's actions.

  • Release Inhibitors: Cromolyn, Nedocromil, and $β_2$ agonists are used for asthma.

  • Receptor Antagonists: Classified by the receptor subtype they block ($H_1$, $H_2$, $H_3$, $H_4$).

• $H_1$ Receptor Antagonists ($H_1RA$)

  • First Generation: Characterized by strong sedative effects and the ability to block autonomic receptors.

    • Ethanolamines: Carbinoxamine, Dimenhydrinate, and Diphenhydramine. Used for anti-motion sickness.

    • Diphenhydramine: Very effective for motion sickness but more sedating than meclizine; used as a local anesthetic for patients allergic to conventional agents.

    • Piperazine Derivatives: Hydroxyzine, Cyclizine, Meclizine. Meclizine is taken $1$ hour before travel for anti-motion sickness.

    • Alkylamines: Brompheniramine, Chlorpheniramine. Often found in OTC cold medicine for anti-muscarinic effects (drying secretions).

    • Phenothiazines: Promethazine. Causes orthostatic hypotension due to $α$-blockade.

    • Miscellaneous: Cyproheptadine. Exhibits anti-serotonin activity ($5-HT_2$ block).

  • Second Generation: Less sedating due to reduced distribution into the Central Nervous System (CNS).

    • Piperidines: Fexofenadine.

    • Miscellaneous: Loratadine, Cetirizine.

    • Withdrawn Agents: Terfenadine and Astemizole were withdrawn due to fatal/lethal arrhythmias when combined with CYP3A4 inhibitors.

• Pharmacokinetics and Pharmacodynamics of $H_1RA$

  • Absorption: Rapidly absorbed; peaks in $1-2 \text{ hours}$.

  • Distribution: Widely distributed; First-generation agents enter the CNS more readily.

  • Metabolism: Occurs in the liver.

  • Duration of Action:

    • First Generation: $4-6 \text{ hours}$.

    • Second Generation (e.g., Meclizine/Cetirizine): $12-24 \text{ hours}$. Can be taken once daily at bedtime.

  • Mechanism of Action: Block histamine actions via reversible competitive binding to $H_1$ receptors.

  • Clinical Uses: Drug of choice for chronic urticaria. Approved for allergic rhinitis (second line after intranasal glucocorticoids). Notably NOT effective for asthma.

• Undesirable Effects of $H_1RA$

  • Sedation: More common in $1^{st}$ generation. Can be therapeutic in pruritus or atopic dermatitis by reducing itch awareness.

  • Seizures: Occur at very high doses.

  • Antimuscarinic Effects: (Esp. Ethanolamines) Leading to vision blurring, urinary retention, and dehydration. Patients should increase fluid intake.

  • Orthostatic Hypotension: Specifically from Promethazine.

• $H_2$ Receptor Antagonists ($H_2RA$)

  • Suffix: Ends in -tidine.

  • Prototype: Ranitidine. (Others: Cimetidine, Famotidine).

  • Pharmacokinetics: Rapidly absorbed; undergoes first-pass hepatic metabolism (Bioavailability approximately $50\%$). Half-life is $1-4 \text{ hours}$, and duration of action is $6-10 \text{ hours}$.

  • Mechanism of Action: Competitive binding to $H_2$ receptors on parietal cells to reduce gastric acid secretion.

  • Cimetidine: Acts as a CYP450 inhibitor; can increase plasma levels of other drugs, leading to toxicity.

  • Clinical Uses: Prophylaxis for surgical patients (IV) and prevention of gastric erosions/hemorrhage in ICU patients. Less effective than Proton Pump Inhibitors (PPI) for GERD but valued for safety.

  • Safety/Adverse Effects: Rare and mild (<3\%); includes headache, fatigue, myalgia, diarrhea, and constipation. Ranitidine long-term use was linked to liver cancer due to carcinogenic NMDA (Zantac brand withdrawn in $2020$).

IV. Serotonin ($5-hydroxytryptamine$ or $5-HT$)

• Synthesis, Storage, and Metabolism

  • Prototype: Prucalopride (Tegaserod was the previous prototype).

  • Synthesis: Derived from the amino acid tryptophan. Hydroxylation of the indole ring at the $C5$ position followed by decarboxylation.

  • Rate-limiting Step: Hydroxylation by tryptophan hydroxylase $1$.

  • Metabolism: Degraded by Monoamine Oxidase (MAO). The major metabolite is $5-hydroxyindoleacetic acid$ (5-HIAA), used as a diagnostic marker for carcinoid tumors.

  • Storage Sites:

    1. ECL cells of GIT: Over $90\%$ of total body serotonin.

    2. Platelets: Involved in clotting.

    3. Brain: Located in the Raphe nuclei of the brainstem. Regulates mood, sleep, appetite, temperature, blood pressure, pain, and vomiting.

    4. Pineal Gland: Serves as a precursor for melatonin.

• Serotonin Receptor Subtypes and Indications

  • $5-HT_{1A}$ Agonist: Buspirone. Used for Generalized Anxiety Disorder (GAD). Unlike diazepam, it is not a regulated benzodiazepine.

  • $5-HT_{1B/1D}$ Agonist: Sumatriptan. Used for acute migraine headache. (Mnemonic: "m1gra1ne = BaD").

  • $5-HT_{1F}$ Agonist: Lasmiditan. New anti-migraine agent (approved $2019$) lacking vasoconstrictor action, making it safer for patients with cardiovascular concerns.

  • $5-HT_2$ Antagonist: Ketanserin. Used for hypertension and carcinoid syndrome.

  • $5-HT_3$ Antagonist: Ondansetron. Prevents chemo-induced and postoperative nausea and vomiting (PONV). (Mnemonic: "nauSea = ch3mo and surg3ry").

  • $5-HT_4$ Agonist: Prucalopride. Used for chronic constipation.

• Serotonin Receptor Agonists (Context and Toxicity)

  • Triptans ($5-HT_{1B/1D}$): First-line for acute severe migraine. Mechanism involves inhibiting the release of CGRP (vasodilating peptide) and stimulating vasoconstriction of intracranial arteries.

  • Triptan Disadvantages: Short duration of action (half-life $2-3 \text{ hours}$, except Frovatriptan at $27 \text{ hours}$); recurring headaches; high cost (Sumatriptan is approximately $\text{PhP } 217$ per tablet).

  • Triptan Contraindications: Coronary heart disease, angina, peripheral vascular disease, Wolff-Parkinson-White syndrome.

  • Flibanserin: $5-HT_{1A}$ agonist for hypoactive sexual desire disorder in women. Contraindicated with alcohol due to risk of severe hypotension.

  • Withdrawn Agonists:

    • Fenfluramine/Dexfenfluramine: Withdrawn in $1997$ due to valvular heart disease and pulmonary hypertension (activation of $5-HT_{2B}$).

    • Lorcaserin: $5-HT_{2C}$ agonist withdrawn in $2007$ due to cancer links.

    • Cisapride/Tegaserod: Cardiotoxicity/MI/Strokes. Cisapride is now compassionate use only.

• Serotonin Syndrome

  • Cause: Excess serotonin levels; often due to drugs like SSRIs, MAOIs, tramadol, meperidine, linezolid, and sumatriptan.

  • Presentation: Hypertension, hyperreflexia, hyperthermia, hyperactive bowel sounds, tremor, clonus, diarrhea, and agitation. Onset within hours.

  • Therapy: Discontinuation of drugs, sedation with benzodiazepines, and Cyproheptadine/Chlorpromazine (5-HT2 block reduces skeletal muscle contractions/hyperreflexia).

• Serotonin Antagonists

  • Synthesis Inhibitors: Telotristat ethyl (diarrhea in carcinoid tumor).

  • Storage Inhibitors: Reserpine (rarely used due to toxicity).

  • Specific Antagonists:

    1. Ketanserin ($5-HT_2$): Primary use for hypertension (via $α$-blockade) and carcinoid syndrome.

    2. Cyproheptadine: Used for carcinoid tumor diarrhea.

    3. Ondansetron ($5-HT_3$): Prototype for nausea. Adverse effects include cardiotoxicity and QT prolongation at high doses.

    4. Alosetron: Used for women with diarrhea-predominant IBS; can cause significant constipation.

V. Ergot Alkaloids

• Origin and History

  • Produced by the fungus Claviceps purpurea infecting wet grains like rye.

  • Ergotism (St. Anthony's Fire): Fiery pain, prolonged vasospasm (gangrene), hallucinations, dementia, and convulsions. Pregnant women suffered abortions due to uterine contractions.

• Pharmacokinetics and Pharmacodynamics

  • Absorption: Variable; improved with caffeine. Oral dose is $10\times$ the IM dose.

  • Receptor Activity: Acts on $5-HT_{1A, 1B, 1D}$, $5-HT_2$, $α$-adrenoreceptors, and Dopamine $D_2$ receptors.

• Clinical Uses

  • Ergotamine (Vasoselective): For migraine; less preferred than triptans due to toxicity (prolonged vasoconstriction/gangrene).

  • Ergonovine (Uteroselective): Stimulates uterine contraction to decrease postpartum hemorrhage if oxytocin fails.

  • Bromocriptine/Cabergoline: $D_2$ agonists for pituitary tumors and peripartum heart failure; do not act on serotonin receptors.

  • LSD (Lysergic Acid Diethylamide): No clinical use; drug of abuse causing hallucinations.

• Toxicity

  • Common: Nausea, vomiting, diarrhea (GI disturbances).

  • Severe: Prolonged vasoconstriction leading to gangrene and amputation. GI infarction.

  • Treatment for Overdose: Large doses of nitroprusside or nitroglycerine.

VI. Vasoactive Peptides

• General Principles

  • Autocoids acting on vascular smooth muscle.

  • Antagonists of vasoconstrictors are used for hypertension.

  • Agonists of vasodilators (like natriuretic peptides) are used for heart failure.

• Renin-Angiotensin System (RAS)

  • Pathway:         $\text{Angiotensinogen} \xrightarrow{\text{Renin}} \text{Angiotensin I} \xrightarrow{\text{ACE}} \text{Angiotensin II}$

  • Angiotensin II ($ANG II$): Potent vasoconstrictor ($40\times$ more potent than norepinephrine). Stimulates release of epinephrine, norepinephrine, and aldosterone.

  • ACE vs. ACE 2: ACE converts $ANG I$ to $ANG II$ (vasoconstriction) and inactivates Bradykinin (vasodilator). $ACE 2$ converts $ANG II$ to $ANG I-7$ (vasodilator) and is the receptor for SARS-CoV-2.

  • Antihypertensive Drugs:

    • ACE Inhibitors: (Captopril, Enalapril) Block ACE. Side effects: cough and angioedema (due to Bradykinin accumulation).

    • ARBs: (Losartan, Valsartan) Block $AT_1$ receptors. No effect on bradykinin. Side effect: hyperkalemia.

    • Renin Inhibitor: Aliskiren.

    • Contraindication: Pregnancy (interferes with fetal renal development).

• Endothelins ($ET$)

  • Potent vasoconstrictors (e.g., $ET-1$).

  • Antagonists: Bosentan and Macitentan for Pulmonary Arterial Hypertension (PAH).

  • Adverse Effects: Hepatotoxicity (Bosentan requires monthly liver tests) and teratogenicity.

• Natriuretic Peptides

  • Physiologic regulators of blood volume. Cause vasodilation, natriuresis, and diuresis.

  • ANP (Atrial): Released by atrial stretch.

  • BNP (Brain/Ventricular): Secreted by heart ventricles. Marker for heart failure (low levels = absence of HF).

  • Drug for Heart Failure: Entresto (Sacubitril + Valsartan). Sacubitril is a Neprilysin inhibitor that prevents the degradation of natriuretic peptides.

  • Vosoritide: CNP analog approved for Achondroplasia (dwarfism) to promote bone growth.

• Kallikrein-Kinin System

  • Produces Bradykinin, a potent vasodilator ($10\times$ more potent than histamine).

  • Icatibant: $B_2$ receptor antagonist used for acute attacks of hereditary angioedema (caused by $C1$-esterase inhibitor deficiency).

• Other Peptides

  • Substance P: Mediates vomiting via $NK_1$ receptors. Aprepitant is an expensive $NK_1$ receptor antagonist used for chemotherapy-induced nausea.

  • CGRP: Implicated in migraines. Ubrogepant and Rimegepant are CGRP antagonists.

  • Vasopressin ($VP$): Desmopressin ($V_2$ agonist) for diabetes insipidus; Tolvaptan ($V_2$ antagonist) for hyponatremia.

VII. Eicosanoids

• Biosynthesis

  • Derived from Arachidonic Acid (a $20$-carbon LCFA) released by Phospholipase $A_2$.

  • Oxygenation via Cyclooxygenase (COX) produces Prostaglandins and Thromboxanes.

  • Oxygenation via Lipoxygenase (LOX) produces Leukotrienes.

• Pharmacologic Agonists and Clinical Uses

  • Obstetrics:

    • Dinoprostone ($PGE_2$): Cervical ripening.

    • Misoprostol ($PGE_1$ analog): Combined with mifepristone as an abortifacient; also prevents NSAID-induced peptic ulcers.

  • Vasculature:

    • Alprostadil ($PGE_1$): Maintains patent ductus arteriosus in neonates with congenital heart defects; also for erectile dysfunction.

    • Epoprostenol ($PGI_2$): For PAH and preventing platelet aggregation in dialysis.

    • Latanoprost ($PGF_{2α}$ derivative): Reduces intraocular pressure in glaucoma.

  • Pulmonology:

    • Montelukast/Zafirlukast: $LTD_4$ (cysteinyl receptor) antagonists for asthma and allergic rhinitis.

• Antagonists and Inhibitors

  • Corticosteroids: Inhibit Phospholipase $A_2$ and COX synthesis.

  • Aspirin: Irreversibly inhibits COX-1 and COX-2. At low doses ($80 \text{ mg/day}$), it kills platelet COX-1 to block $TXA_2$ for CV protection.

  • Indomethacin/Ibuprofen: COX inhibitors used to close a patent ductus arteriosus in normal infants.

  • Zileuton: Inhibits 5-lipoxygenase.

VIII. Nitric Oxide ($NO$)

• Synthesis

  • Synthesized from the amino acid $L-arginine$ in an $O_2$ and NADPH-dependent reaction catalyzed by endothelial Nitric Oxide Synthase (eNOS).

  • Triggered by calcium efflux and calmodulin binding.

• Signaling Mechanism

  • $NO$ binds to iron in heme within Guanylyl Cyclase, activating it to increase $cGMP$ levels.

  • This leads to Protein Kinase G activation, phosphorylation, decreased cytosolic calcium, and subsequent vasorelaxation.

  • In platelets, increased $cGMP$ causes antithrombosis (decreased aggregation).

• Pharmacologic Manipulation

  • NO Donors:

    • Sodium Nitroprusside: Arteriolar and venous vasodilator used for hypertensive emergencies and Ergot poisoning.

    • Nitroglycerin and ISDN: Antianginal agents; decrease cardiac preload.

    • Amyl Nitrite: High lethal hypotension risk if combined with sildenafil.

  • Phosphodiesterase Inhibitors: Sildenafil (Viagra) inhibits PDE-5, the enzyme that degrades $cGMP$, used for erectile dysfunction and PAH.

  • Guanylate Cyclase Stimulators: Riociguat approved for PAH and CTEPH.

  • NO Inhalation: Used for pulmonary hypertension in infants with hypoxic respiratory failure.

IX. Questions & Discussion

• Formative Quiz and Answers

  • Q1: Autacoids are exogenous molecules? A: False (Endogenous).

  • Q2: Safer H1RA for drivers? A: Cetirizine ($2^{nd}$ gen).

  • Q3: H2 receptor inhibitor? A: Famotidine (-tidine).

  • Q4: Sumatriptan is an antagonist? A: False (Agonist).

  • Q5: Prevents postoperative vomiting? A: Ondansetron.

  • Q6: $5-HT_3$ antagonist causing constipation? A: Alosetron.

  • Q7: Ergonovine is first-line for hemorrhage? A: False (Oxytocin is first-line).

  • Q8: ACE inhibitor cough cause? A: Bradykinin accumulation.

  • Q9: Prostaglandin for cervical ripening? A: Dinoprostone.

• Synchronous Questions Discussion

  • LSD: A drug of abuse; no clinical use in schizophrenia.

  • Indomethacin vs. Alprostadil: Indomethacin is used to close a patent ductus arteriosus (PDA); Alprostadil is used to maintain it.

  • Leukotrienes: Potent bronchoconstrictors, not bronchodilators.

  • Bosentan SE: Can cause hepatotoxicity.

  • Aprepitant: Substance P antagonist for puking; quite expensive.