Pharmacotherapeutics: Autacoids, Biogenic Amines, Ergot Alkaloids, Eicosanoids, and Vasoactive Peptides

Practice flashcards created from lecture notes covering autacoid classification, histamine kinetics and receptor subtypes, antihistamines, serotonin pathways, ergot alkaloids, eicosanoids, and vasoactive peptides.

What is the etymological origin and biological definition of the term autacoid?

Derived from the Greek words autos (self) and akos (healing or remedy), autacoids are endogenous local repair agents produced by diverse non-specialized cells across virtually all body tissues that act near their site of synthesis and have a very short half-life.

How do autacoids differ from hormones regarding site of action, mode of transport, and half-life?

Autacoids act locally via paracrine or autocrine mechanisms, diffuse through local interstitial fluid without relying on systemic circulation, and have a very short half-life. Hormones act on distant target organs via endocrine action, travel through the bloodstream, and have a longer half-life.

How is histamine synthesized in the human body?

Histamine is synthesized from the amino acid L-histidine via decarboxylation catalyzed by the enzyme L-histidine decarboxylase (HDC), requiring Pyridoxal Phosphate (Vitamin B6) as a coenzyme.

What are the key enzymes and final metabolites involved in the intracellular and extracellular pathways of histamine degradation?

The intracellular pathway (predominant in the CNS and parenchymal tissues) uses Histamine-N-Methyltransferase (HNMT) to produce N-methylimidazole acetic acid. The extracellular pathway (predominant in the GI tract, blood plasma, and ECF) uses Diamine Oxidase (DAO) to produce Imidazole acetic acid (IAA).

What signal transduction pathways, primary effectors, and physiological responses are associated with H1 and H2 histamine receptor subtypes?

H1 receptors couple to $G_q$ (PLC $\rightarrow$ IP3/DAG $\rightarrow \uparrow Ca^{2+}$), stimulating smooth muscle contraction, bronchoconstriction, and vascular permeability. H2 receptors couple to $G_s$ (AC $\rightarrow \uparrow cAMP \rightarrow$ PKA), stimulating gastric acid secretion and cardiac rate/contractility.

What signal transduction pathways, cellular locations, and physiological roles are associated with H3 and H4 histamine receptor subtypes?

H3 receptors couple to $G_i$ ($\downarrow cAMP$) on CNS neurons, functioning as presynaptic autoreceptors to inhibit neurotransmitter release and suppress appetite. H4 receptors couple to $G_i$ ($\downarrow cAMP$, $\uparrow Ca^{2+}$ influx) on hematopoietic cells, mediating chemotaxis and inflammation.

What three skin reactions constitute the classic Triple Response of Lewis following intradermal histamine injection?

1. Red Spot (localized hyperemia due to direct microvascular vasodilation), 2. Flare (axon reflex propagating sensory impulses to release peripheral vasodilators), and 3. Wheal (edema from endothelial cell separation and fluid transudation into interstitial space).

How does scombroid fish poisoning occur and why does thermal cooking fail to prevent it?

Scombroid fish (tuna, mackerel, mahi-mahi) contain high levels of L-histidine. If stored improperly ($>4\,^\circ\text{C}$), surface bacteria proliferate and produce histidine decarboxylase, converting histidine to histamine. Histamine is heat-stable, so cooking kills the bacteria but leaves the toxic histamine autacoid intact.

Why is Epinephrine the drug of choice for immediate treatment of anaphylaxis over antihistamines or corticosteroids?

Epinephrine acts as a full agonist at adrenoreceptors: $\alpha_1$ agonism induces vasoconstriction to raise blood pressure and reduce airway edema, while $\beta_2$ agonism causes bronchodilation and suppresses ongoing mast cell degranulation, functionally reversing all systemic effects of histamine.

What are the correct operational steps for administering an EpiPen?

1. Grasp injector with orange tip pointing down. 2. Remove blue safety cap. 3. Place orange tip against outer thigh middle. 4. Swing and push firmly into thigh until it clicks. 5. Hold in place for $3\,s$ before removing.

What is the mechanism of action and clinical application of release inhibitors such as Cromolyn sodium and Nedocromil sodium?

They block delayed chloride channels and inhibit $Ca^{2+}$ influx in mast cells and basophils, preventing secretory granule fusion and exocytosis of histamine and leukotrienes. They are strictly prophylactic agents used regularly for asthma and allergic rhinitis prevention.

What is meant by inverse agonism as it applies to H1 antihistamines?

H1 antihistamines bind preferentially to the inactive conformation of the G-protein coupled H1 receptor, stabilizing it in an inactive state and downregulating constitutive baseline signaling, rather than simply blocking histamine binding.

Why are 2nd-generation H1 antihistamines non-sedating compared to 1st-generation H1 antihistamines?

2nd-generation antihistamines have lower lipophilicity, higher molecular weight, exist ionized at physiological pH, have lower affinity for central H1 receptors, and are active substrates for the P-glycoprotein efflux transporter at the blood-brain barrier.

What off-target receptor interactions produce the side effects of dry mouth, orthostatic hypotension, and appetite stimulation seen with 1st-generation antihistamines?

Dry mouth is caused by muscarinic ($M_1\text{--}M_5$) receptor antagonism; orthostatic hypotension is caused by $\alpha_1$ adrenoceptor antagonism; appetite stimulation is caused by serotonin ($5\text{-}HT_{2A}$ or $5\text{-}HT_{2C}$) and central H1 receptor blockade.

What is the signal transduction mechanism of histamine-stimulated gastric acid secretion, and how do H2 receptor antagonists block it?

Histamine binds H2 receptors on parietal cells $\rightarrow G_s \rightarrow \uparrow cAMP \rightarrow$ PKA activation $\rightarrow H^+/K^+\text{-}ATPase$ pump activity. H2 antagonists (e.g., Famotidine) selectively stabilize the inactive H2 receptor state to decrease baseline $cAMP$ and acid production.

How is Serotonin (5-HT) synthesized, stored, and inactivated in human tissues?

Synthesized from L-tryptophan by hydroxylation and decarboxylation. Transported into vesicles for storage via VMAT2 (in enterochromaffin cells and CNS neurons) and taken up into blood platelets via SERT. Inactivated primarily by Monoamine Oxidase A (MAO-A) into 5-HIAA, which is excreted in urine.

What structural and functional feature uniquely distinguishes the 5-HT3 receptor from all other serotonin receptor subtypes?

The 5-HT3 receptor is a ligand-gated $Na^+/K^+$ ion channel that causes direct neuronal depolarization, whereas all other serotonin receptors (5-HT1, 5-HT2, 5-HT4, 5-HT5, 5-HT6, 5-HT7) are G-protein coupled receptors (GPCRs).

What are the mechanisms and primary clinical indications for Sumatriptan, Ondansetron, and Cyproheptadine?

Sumatriptan ($5\text{-}HT_{1B/1D}$ agonist) causes cranial vasoconstriction for acute migraine relief. Ondansetron ($5\text{-}HT_3$ antagonist) acts centrally and peripherally to treat chemotherapy-induced and postoperative nausea/vomiting. Cyproheptadine ($5\text{-}HT_{2A}$ and H1 antagonist) serves as an appetite stimulant.

What is Ergotism (St. Anthony's Fire) and what receptor actions of ergot alkaloids cause its manifestations?

Ergotism is toxic poisoning caused by ingesting Claviceps purpurea fungus on grains. Potent $\alpha_1$-adrenergic and $5\text{-}HT_{2A}$ partial agonist effects cause prolonged, severe peripheral vasospasm leading to gangrene, while CNS actions cause dementia and florid hallucinations.

What are the pharmacological actions and clinical indications for Ergonovine and Bromocriptine?

Ergonovine acts as an $\alpha_1$ and $5\text{-}HT_2$ agonist to induce strong uterine smooth muscle contractions for controlling postpartum hemorrhage. Bromocriptine acts as a $D_2$ dopamine receptor agonist in the anterior pituitary to suppress prolactin secretion in hyperprolactinemia.

What initial step liberates arachidonic acid for eicosanoid synthesis, and what are the two main metabolic pathways?

Phospholipase A2 cleaves membrane phospholipids to release esterified arachidonic acid. It is metabolized by Cyclooxygenases (COX-1/COX-2) into prostanoids (prostaglandins, prostacyclin, thromboxanes) or Lipoxygenases (LOX) into leukotrienes, HETEs, and lipoxins.

How do COX-1 and COX-2 differ in expression pattern and physiological roles?

COX-1 is constitutively expressed (full-time) in most tissues to generate prostanoids for physiological housekeeping, such as gastric mucosal cytoprotection and platelet aggregation. COX-2 is inducible (part-time) by cytokines, mitogens, and shear stress during inflammation and tissue injury.

What is the mechanism of action of low-dose aspirin as a cardioprotective antithrombotic agent?

Low-dose aspirin irreversibly acetylates COX-1 in platelets, permanently blocking Thromboxane A2 (TXA2) synthesis and inhibiting platelet aggregation for the lifetime of the non-nucleated platelet ($8\text{--}11\,\text{days}$).

What are the mechanisms of action for Zileuton and Montelukast in treating asthma?

Zileuton inhibits the enzyme 5-Lipoxygenase (5-LOX), preventing initial formation of 5-HPETE and leukotrienes. Montelukast is a competitive antagonist at the CystLT1 receptor, blocking the actions of LTD4.

What are the therapeutic indications for prostanoid mimetics Misoprostol, Alprostadil, and Latanoprost?

Misoprostol (PGE1) prevents NSAID-induced peptic ulcers and acts as an abortifacient/cervical ripener. Alprostadil (PGE1) maintains patent ductus arteriosus in congenital heart defects. Latanoprost (PGF2a) increases aqueous humor outflow to treat open-angle glaucoma.

Why do ACE inhibitors cause dry cough and angioedema while ARBs do not?

ACE (Kininase II) metabolizes and inactivates Bradykinin. ACE inhibitors block ACE, causing systemic accumulation of Bradykinin and Substance P which stimulate sensory C-irritant fibers in the lungs. ARBs competitively block AT1 receptors directly without altering bradykinin breakdown.

What tissue locations, signaling mechanisms, and physiological effects characterize V1a and V2 vasopressin receptors?

V1a receptors exist on vascular smooth muscle ($G_q \rightarrow \uparrow IP_3/Ca^{2+}$) to cause potent vasoconstriction. V2 receptors exist on renal collecting duct cells ($G_s \rightarrow \uparrow cAMP$) to trigger Aquaporin-2 channel insertion, increasing free-water reabsorption.

What causes Hereditary Angioedema (HAE) and what selective B2 receptor antagonist is indicated for acute attacks?

HAE is caused by C1-esterase inhibitor deficiency, leading to unchecked plasma kallikrein activity and excessive Bradykinin production. Acute attacks are treated with Icatibant, a selective kinin B2 receptor antagonist given subcutaneously.

What is the mechanism of action of Sacubitril/Valsartan (ARNI) in managing heart failure with reduced ejection fraction?

Sacubitril inhibits Neprilysin (NEP) to decrease degradation of endogenous vasodilatory natriuretic peptides (ANP, BNP), raising intracellular $cGMP$. Valsartan selectively blocks AT1 receptors to suppress renin-angiotensin-aldosterone vasoconstriction and cardiac remodeling.

How do Gepants and anti-CGRP monoclonal antibodies differ from Triptans and Ergotamines regarding cardiovascular safety?

Gepants (e.g., Ubrogepant) and anti-CGRP mAbs (e.g., Erenumab) antagonize CGRP signaling without causing direct vasoconstriction, making them safe for migraine sufferers with underlying cardiovascular or cerebrovascular disease.