Autacoid and their Antagonists

Autacoid and their Antagonists

H1 receptor antagonists

Classification of H₁ Antihistaminic Drugs based on their Clinical use:-

1.      Potent and sedative: Ex:  Diphenhydramine Dimenhydrinate Promethazine

2.      Potent but less sedative: Ex: Chlorpheniramine

3.      Less potent and less sedative Ex:Mepyramine

4.      Non-sedative Ex: Fexofenadine, Loratadine, Cetirizine, Acrivastine.

Pharmacological action of H1 receptor antagonists:-

a. Smooth Muscle. H₁ antagonists inhibit effects of histamine on smooth muscles, i.e., constriction smooth muscle of respiratory, GIT, bronchi, uterus, and blood vessels and augments salivary section.

b. Capillary Permeability. H₁ antagonists strongly blocks increased capillary permeability and formation of edema and wheal brought about by histamine.

c. Flare and Itch The flare component of triple response and itching caused by intradermal injection of histamine are two different manifestations of action of histamine on nerve endings. H₁ antagonists suppress both.

d. Exocrine Glands. H₁ antagonists do not suppress gastric secretion, but they do suppress histamine-evoked salivary, lacrimal, and other exocrine secretions. The antimuscarinic property may contribute to lessened secretion in cholinergically innervated glands and reduce ongoing secretion.

e. ANS: Antihistamines exhibit muscarininc blocking activity. Dryness of mouth is common side effect. Antihistimincs, like antazoline and phenidamne exert adrenergic blocking effect.

f. Local Anesthetic Effect.H₁ antagonists have local anesthetic activity, but has no clinical applications.

g. CNS:-older antihistamines produce variable degree of CNS depression and depends on ability to penetrate BBB and its affinity for central H₁ receptors, conventional doses produce restlessness, tremors, and insomnia and activate latent epilepsy.

h. Sedation and hypnosis: CNS depression is common side effect and induces varying degree of sedation, drowsiness and sleep. Sedation is beneficial in treatment of allergic reactions. Drugs like promethazine and diphenhydramine are potent sedatives and hypnotics. Sedation is accompanied by inability to concentrate, dizziness and disturbance of co-ordination.

i. Antiemetic and antimotion sickness effects:- Motion sickness, attributed to vestibular disturbance, is benefited by diphenhydramine, dimenhydrinate, promethazine and piperazine antihistaminic. Vomiting due to labyrinthitis and fenestration operation responds to antihistaminic. Antihistaminic except phenothiazines used in treating emesis due to jaundice, radiation and alkylating agents.

j. Cardiovascular system: on oral administration no effect, on I.V administration of diphenhydramine, antazoline, methapyrilene and triplennamine may produce quinidine like effect due to their membrane stabilizing action and causes fall in BP.

k. Antiallegeric action: Manifestation of immediate hypersensitivity (type 1 reaction) are suppressed, urticaria, itching and angio edema are well controlled. Anaphylactic fall in BP is partially prevented.

Absorption, Fate, and Excretion

Well absorbed after oral administration, with peak blood levels occurs within 1 to 2 hours; therapeutic effect lasts for 4 to 6 hours. Metabolized in liver by hydroxylation and metabolites and parent compound are excreted in urine.

Adverse Effects:

CNS: Common side effect is sedation and hypnosis, and includes dizziness, tinnitus, lassitude, incoordination, fatigue, blurred vision, diplopia, euphoria, nervousness, insomnia, and tremors.

Antimuscarinic effects: dryness of mouth, blurring of vision bladder disturbances and rarely impotence.

GI: Nausea, vomiting and epigatric distress may occur occasionally.

Cardiac: Hypotension and sense of tightness in chest may develop rarely.

Misc: Antihistaminics, in spite of their antiallergic properties may themselves produce allergic manifestations.

Therapeutic Uses:-

Allergic Diseases H₁ antagonists are useful in acute types of allergy that present with symptoms of seasonal rhinitis, urticaria, and conjunctivitis (hay fever, pollinosis), and relieves sneezing, rhinorrhea, and itching of eyes, nose, and throat. Their effect is confined to suppression of symptoms attributable to histamine released by antigen-antibody reaction.

Antiinflammatory effects:- H₁ antihistamines is investigated for potential antiinflammatory properties.

Chronic urticariaCertain allergic dermatoses respond to H₁ antagonists. Benefit is most striking in acute urticaria, although, itching in condition is better controlled than edema and erythema.

Pruritides: H₁ antagonists have a place in treatment of pruritus. Relief may be obtained in many patients suffering atopic dermatitis and contact dermatitis and in conditions such as insect bites and poison ivy.

Common Cold H₁ antagonists are without value in combating the common cold. The weak anticholinergic effects of older agents may tend to lessen rhinorrhea, but this drying effect may do more harm than good, as may their tendency to induce somnolence.

Motion Sickness: Although scopolamine, given orally, parenterally, or transdermally, is most effective of all drugs for prophylaxis and treatment of motion sickness. The antihistaminic drugs with greatest effectiveness in this application are diphenhydramine and promethazine. Dimenhydrinate, is used for treatment of motion sickness.

Parkinsonism: - Diphenhydramine can reverse the extrapyramidal side effects caused by phenothiazines. The anticholinergic actions of this agent are used in early stages of Parkinson's disease, but it is less effective than other agents.

Sedation, hypnotics and anxiolytics: H₁-receptor antagonists with CNS depressant action are used as sedative and to induce sleep. H₁ antagonists like, diphenhydramine, used for insomnia. The sedative and mild antianxiety activities of hydroxyzine and diphenhydramine have contributed to their use as weak anxiolytics.

Histamine

Pharmacological Effects

Effects on Histamine Release. H₂-receptor stimulation increases cyclic AMP and leads to feedback inhibition of histamine release from mast cells and basophils. Activation of H₃ and H₄ receptors decreases cellular cyclic AMP.

Cardiovascular System. Histamine causes dilation of resistance vessels, an increase in capillary permeability, and overall fall in systemic blood pressure. In some vascular beds, histamine will constrict veins, contributing to the extravasation of fluid and edema formation upstream of the capillaries and postcapillary venules.

Vasodilation: It involves both H₁ and H₂ receptors distributed throughout resistance vessels in most vascular beds. H₁ receptors have higher affinity for histamine and mediate endothelium-NO-dependent dilation that is rapid in onset and short-lived. Activation of H₂ receptors causes dilation that develops more slowly and is more sustained.

Triple Response of Lewis If histamine is injected intradermally, it elicits a phenomenon known as triple response. This consists of

(1) Red spot: due to intense capillary dilatation.

(2) Wheal: due to exudation of fluid from capillaries and venules.

(3) Flare: redness in surrounding area due to arteriolar dilation meditated by axon reflex.

Constriction of Larger Vessels. Histamine tends to constrict larger blood vessels. H₁-receptor-mediated constriction may occur in some veins and in conduit coronary arteries.

Histamine Shock Histamine given in large doses or released during systemic anaphylaxis causes a profound and progressive fall in blood pressure. As the small blood vessels dilate, they trap large amounts of blood, and as their permeability increases, plasma escapes from the circulation.

Extravascular Smooth Muscle Histamine stimulates or relaxes various smooth muscles. Contraction is due to activation of H₁ receptors, and relaxation is due to activation of H₂ receptors. Minute doses of histamine also will evoke intense bronchoconstriction in patients with bronchial asthma and certain other pulmonary diseases.

Exocrine Glands Histamine is an important physiological regulator of gastric acid secretion. This effect is mediated by H₂ receptors.

Absorption, Fate, and Excretion

Absorbed from all sites and is very stable. It undergoes first pass metabolism. Metabolized in liver by converting into methyl histamine by imidazole-n-methyl transferase and further converted by MOA-B into 1-Methyl imidazole acetic acid.

Adverse effects of histamine release are like those following administration of histamine, are dose-related. Flushing, hypotension, tachycardia, headache, wheals, bronchoconstriction, and gastrointestinal upset.

Histamine should not be given to patients with asthma or to patients with active ulcer disease or gastrointestinal bleeding.

Clinical Uses of Histamine

a.       It has only minor uses in clinical medicine.

b.      It has been used to assess bronchial hyperreactivity, although this test may be quite hazardous for asthmatics. 

c.       Used as a positive control injection for allergy skin testing.

Therapeutic uses of 5-HT receptors

5-HT receptors are classified based on data derived from cloning, signal transduction mechanism and pharmacological specificity.

5-HT₁ Receptors: occurs in brain and subtypes5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E & 5-HT_1F. The 5-HT_1A receptor is found in brain; it functions as inhibitory, somatodendritic autoreceptor on cell bodies of serotonergic neurons have relation to mood and behavior. 5-HT_1D receptor, present in cerebral blood vessel and important in migraine.

5-HT₂ Receptors The 3 subtypes of 5-HT_{2A, 2B, 2C}receptors are linked to phospholipase C and stimulates IP₃ formation. 5-HT_2A receptors are distributed in CNS. The peripheral effects of 5-HT on smooth muscles and platelets are stimulated by 5-HT_2A receptors. 5-HT_2C receptor present on vascular endothelium produces vasodilatation through EDRF releases.

5-HT₃ Receptors occurs in peripheral nervous system, particularly on nociceptive sensory neurons and on autonomic and enteric neurons.

5-HT₄ Receptors are present in brain and peripheral organs such as GIT, bladder and heat. In GIT, they produce neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis.

The other resecptors 5-HT_5, 5-HT₆, and 5-HT₇ are closely related to 5-HT₄ receptors, they are mainly located in brain, but their functional roles are not determined.

Agonists:

Drug	5-HT receptor	uses
Ergotamine	All 5-HT1, 2A, 2B	Acute attack of migraine
LSD	5-HT1A, 2A, 2C	Hallucinogen
Triptane	5-HT1B, 1D	Acute attacks of migraine
Buspirone	5-HT1A	Anxiety states
Cisapride	5-HT4,	Gastroesophageal reflux disease
Metoclopramide	5-HT4	GERD, gastroparesis
Tegaserod	5-HT4	Irritable bowel syndrome

Antagonists:

Drug	5-HT receptor	uses
Cyproheptadine	5-HT2A,	Migraine prophylaxis, carcinoid syndrome, postgastrectomy dumping syndrome
Methysergide	5-HT2A, 2C	carcinoid syndrome, postgastrectomy dumping syndrome
Ketanserin	5-HT2A, 2C	Acute attacks of migraine
Mianserin	5-HT3, 2A, 2C	Antidepressant
Clozapine	5-HT2A, 2C	Schizophrenia
Metoclopramide	5-HT3	Antiemetic,
Ondansetron	5-HT3	Antiemetic,

H2 receptor blocker

Ex: Ranitidine, cimetidine, Famotidine.

Pharmacodynamics

H₂ antagonists exhibit competitive inhibition at parietal cell H₂ receptor and suppress basal and meal-stimulated acid secretion. They are highly selective and do not affect H₁ or H₃ receptors. The volume of gastric secretion and concentration of pepsin are also reduced.

H₂ antagonists reduce acid secretion stimulated by histamine as well as by gastrin and cholinomimetic agents through two mechanisms. First, histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to parietal cell H₂ receptor. Second, direct stimulation of parietal cell by gastrin or acetylcholine results in diminished acid secretion in presence of H₂-receptor blockade.

H₂ antagonists are effective at inhibiting nocturnal acid secretion, but have impact on meal-stimulated acid secretion. Thus, they block 90% of nocturnal acid, but only 60–80% of daytime acid secretion. Therefore, nocturnal and fasting intragastric pH is raised to 4–5.

Pharmacokinetics: Rapidly absorbed after oral administration, with peak serum concentrations within 1 to 3 hours. Absorption may be enhanced by food or decreased by antacids. Therapeutic levels are achieved rapidly after intravenous dosing. Small percentage is protein-bound. Undergoes metabolism in liver. The kidneys excrete drugs and metabolites by filtration and renal tubular secretion.

Clinical Uses

Gastroesophageal Reflux Disease (GERD): Patients with heartburn or dyspepsia may take H₂ antagonists. It may be taken prophylactically before meals to reduce heartburn. In patients with erosive esophagitis, and affords healing.

Peptic Ulcer Disease:Nocturnal acid suppression by drug affords effective ulcer healing in patients with uncomplicated gastric and duodenal ulcers. Hence, administered for acute, uncomplicated ulcers, resulting in ulcer healing. For patients with ulcers caused by aspirin or other NSAIDs, H₂ antagonists provide rapid ulcer healing.

Nonulcer Dyspepsia:H₂ antagonists are used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer.

Prevention of Bleeding from Stress-Related Gastritis: H₂-receptor antagonists reduce incidence of bleeding from stress-related gastritis in seriously ill patients in intensive care unit.

Adverse Effects

a.       Common are diarrhea, headache, fatigue, myalgias, and constipation.

b.      Central Nervous System:Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H₂ antagonists. These events may be more common with cimetidine.

c.       Endocrine Effects:Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women.

d.      Pregnancy and Nursing Mothers: No known harmful effects on fetus, but, cross placenta. Therefore, they should not be administered to pregnant women unless absolutely necessary. The H₂ antagonists are secreted into breast milk and affect nursing infants.

e.       Others:H₂ antagonists may rarely cause blood dyscrasias. Rapid intravenous infusion may cause bradycardia and hypotension through blockade of cardiac H₂ receptors.

Drug Interactions: H₂ antagonists compete with certain drugs (eg, procainamide) for renal tubular secretion.

Lipid derived autacoids

PGs and LTs (eicosanoids) are biological active derivatives of 20 carbon atom polyunsaturated essential fatty acids that are released from cell membrane phospholipids. They are major lipid derived autacoids.

Pharmacological Properties of Eicosanoids

Cardiovascular System In most vascular beds, PGE₂ elicits vasodilation and drop in blood pressure, although vasoconstrictor effects are reported. Infusion of PGD₂ results in flushing, nasal stuffiness, and hypotension; subsequent formation of F-ring metabolites may result in hypertension. Responses to PGF_2α vary with species and vascular bed; it is a potent constrictor of both pulmonary arteries and veins.

PGI₂ relaxes vascular smooth muscle, causing prominent hypotension and reflex tachycardia on i.v. administration. TxA₂ is a potent vasoconstrictor.

LTC₄ and LTD₄ cause hypotension. This may result partly from a decrease in intravascular volume and also from decreased cardiac contractility secondary to a marked LT-induced reduction in coronary blood flow.  LTC₄ and LTD₄ constrict arterioles and reduce exudation of plasma.

Platelets. Low concentrations of PGE₂ enhance and higher concentrations inhibit platelet aggregation. Both PGI₂ and PGD₂ inhibit aggregation of platelets in vitro.

Inflammation and Immunity. Eicosanoids play a major role in inflammatory and immune responses. While LTs are proinflammatory and lipoxins antiinflammatory, prostanoids can exert both kinds of activity.

LTB₄ is a potent chemotactic agent for polymorphonuclear leukocytes, eosinophils, and monocytes. In higher concentrations, LTB₄ stimulates aggregation of polymorphonuclear leukocytes and promotes degranulation and generation of superoxide.

Prostaglandins inhibit lymphocyte function and proliferation, suppressing immune response. PGE₂ depresses humoral antibody response by inhibiting differentiation of B-lymphocytes into antibody-secreting plasma cells. PGE₂ and TxA₂ also may play a role in T-lymphocyte development by regulating apoptosis of immature thymocytes. PGD₂, a product of mast cells, is potent chemoattractant for eosinophils and induces chemotaxis and migration of Th2 lymphocytes.

Smooth Muscle. Prostaglandins contract or relax smooth muscles besides those of the vasculature. The LTs contract most smooth muscles.

Bronchial and Tracheal Muscle PGF_2α and PGD₂ contract and PGE₂ and PGI₂ relax bronchial and tracheal muscle. Prostaglandin endoperoxides and TxA₂ constrict human bronchial smooth muscle. LTC₄ and its metabolites LTD₄ and LTE₄ are bronchoconstrictors in many species, including humans. These LTs stimulate bronchial mucus secretion and cause mucosal edema.

PGI₂ causes bronchodilation in most species; human bronchial tissue is particularly sensitive, and PGI₂ antagonizes bronchoconstriction induced by other agents.

Uterus. Strips of nonpregnant human uterus are contracted by PGF_2α and TxA₂ but are relaxed by E prostaglandins. Sensitivity to the contractile response is most prominent before menstruation, whereas relaxation is greatest at midcycle. Low concentrations of PGE₂. PGE₂, together with oxytocin, is essential for onset of parturition.

Gastrointestinal Muscle. The E and F prostaglandins stimulate contraction of longitudinal muscle from stomach to colon. Prostaglandin endoperoxides, TxA₂, and PGI₂ also produce contraction but are less active. Circular muscle generally relaxes in response to PGE₂ and contracts in response to PGF_2α. The LTs have potent contractile effects. PGs reduce transit time in the small intestine and colon. The E and F prostaglandins stimulate the movement of water and electrolytes into the intestinal lumen.

Gastric and Intestinal Secretions In stomach, PGE₂ and PGI₂ contribute to increased mucus secretion, reduced acid secretion, and reduced pepsin content. These effects result from their vasodilatory properties and probable direct effects on secretory cells. PGE₂ and its analogs also inhibit gastric damage caused by a variety of ulcerogenic agents and promote healing of duodenal and gastric ulcers.

Kidney and Urine Formation PGs influence renal salt and water excretion by alterations in renal blood flow and by direct effects on renal tubules. PGE₂ and PGI₂ infused directly into the renal arteries of dogs increase renal blood flow and provoke diuresis, natriuresis, and kaliuresis, with little change in glomerular filtration rate. PGEs inhibit water reabsorption induced by antidiuretic hormone. PGI₂, PGE₂, and PGD₂ stimulate renin secretion from the renal cortex apparently through a direct effect on the granular juxtaglomerular cells.

Eye PGF_2α induces constriction of the iris sphincter muscle, and decrease intraocular pressure (IOP) by increasing the aqueous humor outflow of the eye.

Central Nervous System The induction of fever by a range of endogenous and exogenous pyrogens appears to be mediated by PGE₂. Exogenous PGF_2α and PGI₂ induce fever but do not contribute to the pyretic response. PGD₂ and TxA₂ do not induce fever. PGD₂ also appears to act on basal forebrain to mediate an increase in extracellular adenosine that, in turn, facilitates induction of sleep.

Centrally, PGE₂ can increase excitability in pain transmission neuronal pathways in the spinal cord. Hyperalgesia also is produced by LTB₄.

Endocrine System systemic administration of PGE₂ increases circulating concentrations of ACTH, growth hormone, prolactin, and gonadotropins. Other effects include stimulation of steroid production by the adrenals, stimulation of insulin release, and thyrotropin-like effects on the thyroid. The critical role of PGF_2α in parturition relies on its ability to induce an oxytocin-dependent decline in progesterone levels. PGE₂ works as part of a positive-feedback loop to induce oocyte maturation required for fertilization during and after ovulation.

LOX metabolites also have endocrine effects. 12-HETE stimulates the release of aldosterone from the adrenal cortex and mediates a portion of the aldosterone release stimulated by angiotensin II, but not that which occurs in response to ACTH.

Bone. PGs are strong modulators of bone metabolism. PGE₂ stimulates bone formation and resorption through osteoblastic and osteoclastic activities affecting bone strength and composition.

Therapeutic Uses

Therapeutic Abortion. When given early in pregnancy, their action as abortifacients may be variable and often incomplete and accompanied by adverse effects. PGs appear, however, to be of value in missed abortion and molar gestation, and they have been used widely for the induction of midtrimester abortion.

PGE₂ or PGF_2alpha can induce labor at term. However, they may have more value when used to facilitate labor by promoting ripening and dilation of the cervix.

Gastric Cytoprotection. The capacity of several PG analogs to suppress gastric ulceration is a property of therapeutic importance.

Impotence. PGE₁ may be used in treatment of impotence. Intracavernous injection of PGE₁ causes complete or partial erection in impotent patients. The erection lasts for 1 to 3 hours and is sufficient for sexual intercourse.

Maintenance of Patent Ductus Arteriosus. The ductus arteriosus in neonates is highly sensitive to vasodilation by PGE₁. Maintenance of a patent ductus may be important hemodynamically in some neonates with congenital heart disease.

Pulmonary Hypertension is a rare idiopathic disease that mainly affects young adults. It leads to right-sided heart failure and frequently is fatal.

Ondansetron

Ondansetron is potent antagonist of 5-HT₃ receptors, found peripherally on vagal nerve terminals and centrally in CTZ. During chemotherapy that induces vomiting, mucosal enterochromaffin cells in the GI tract release serotonin, which stimulates 5-HT₃ receptors. This cause vagal afferent discharge, inducing vomiting.These agents do not inhibit dopamine or muscarinic receptors. They do not have effects on esophageal or gastric motility but may slow colonic transit.

Mechanism of Action: In binding to 5-HT₃ receptors, ondansetron and granisetron block serotonin stimulation, hence vomiting, after emetogenic stimuli such as cisplatin.

Pharmacokinetics: Oral bioavailability is 60-70% undergoes first pass metabolism.t_1/2 is 3-5 hours and duration of action is 4-12 hours. Excreted through urine and faeces.

Adverse effects: Constipation, diarrhea, abdominal pain, skin rashes, and allergic reactions. Headache is the most frequently reported adverse effect.

Uses: Vomiting and nausea associated with cancer chemotherapy and radio therapy, prophylaxis and treatment of post-operative nausea and vomiting.

Serotonin antagonists

The ability to antagonize actions of 5-HT is found in drugs like Ergot derivatives (ergotamine, LSD, methysergide) adrenergic alpha blocker (Phenoxybenzamine) antihistamines (cyproheptadine, cinnarizine) chlorpromazine, morphine. But these are nonselective and interact with several other receptors.

a.       Phenoxybenzamine has a long-lasting blocking action at 5-HT₂ receptors.

b.      Cyproheptadine has potent H₁ receptor-blocking as well as 5-HT₂ blocking actions. It is used in treatment of smooth muscle manifestations of carcinoid tumor and in postgastrectomy dumping syndrome. It is also preferred drug in cold-induced urticaria.

c.       Ketanserin blocks 5-HT_1c receptors & 5-HT₂ receptors on platelets and antagonizes platelet aggregation promoted by serotonin. It is used for treatment of hypertension and vasospastic conditions.

d.      Ritanserin, 5-HT₂ antagonist, it alters bleeding time and reduce thromboxane formation, presumably by altering platelet function.

e.       Ondansetron is prototypical 5-HT₃ antagonist.

Uses: Vomiting and nausea associated with cancer chemotherapy and radio therapy, prophylaxis and treatment of post-operative nausea and vomiting.

Therapeutic uses of serotonin antagonists:

a.       Relief of pruritis,

b.      Migraine prophylaxis

c.       Treatment of postgastrectomy dumping syndrome and carcinoid syndrome

d.      Symptomatic relief in season and perennial pollinosis

e.       As an appetite stimulant in certain conditions.

f.       In Cushing’s disease.

5 HT₃antagonist

5-HT₃-receptor antagonists have potent antiemetic properties, mediated through central 5-HT₃-receptor blockade in vomiting center and CTZ and blockade of peripheral 5-HT₃ receptors on extrinsic intestinal vagal and spinal afferent nerves. These agents do not inhibit dopamine or muscarinic receptors. They do not have effects on esophageal or gastric motility but may slow colonic transit.

Ex: ondansetron, granisetron, dolasetron, and palonosetron.

Clinical Uses of 5-HT₃-receptor antagonists

a.       Used for prevention of acute Chemotherapy-Induced Nausea and Vomiting

b.      Used to prevent or treat postoperative and postradiation nausea and vomiting.

c.       Used in treatment of nausea and vomiting due to acute or chronic medical illness or acute gastroenteritis.

Adverse Effects:Headache, dizziness, and constipation. All three agents cause a small but statistically significant prolongation of QT interval.

Serotonin

5-Hydroxytryptamine (5-HT, serotonin) is regulator of smooth muscle in CV system and GIT, an enhancer of platelet aggregation, and a neurotransmitter in CNS.

Source: 5-HT is found in high concentrations in enterochromaffin cells throughout GIT, in storage granules in platelets, and broadly throughout CNS. 

Types: Fourteen 5-HT-receptor subtypes have been delineated by pharmacological analyses and cDNA cloning. The 5-HT₁, 5-HT₂, and 5-HT_4-7 receptor families are members of superfamily of GPCRs.

Serotonin exerts many actions like histamine. The actions are mediated through a remarkably large number of cell membrane receptors. 5-HT is not used therapeutically.

Cyproheptadine

Cyproheptadine is effective H₁-receptor antagonist. It binds to 5-HT_2A receptors, and shows 5-HT blocking activity on smooth muscle.

The actions are predictable from its H₁ histamine and serotonin receptor affinities. It prevents smooth muscle effects of both amines but has no effect on gastric secretion stimulated by histamine. It has significant antimuscarinic effects and causes sedation. It also has weak anticholinergic activity and possesses mild CNS depressant properties.

Used in treatment of smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria. It is of value in serotonin syndrome, but is available only in tablet form; it must be crushed and administered by stomach tube in unconscious patients.

Side effects: Drowsiness, weight gain and increased growth in children is observed and attributed to impaired regulation of growth-hormone secretion.

Non sedative antihistamines

Second-Generation antihistamines are also called as non-sedative antihistamines.

May be defined as those H1 receptor blockers and has following properties:

a)      Higher H1 selectivity: no anticholinergic side effects.

b)      Absence of CNS depressant property.

c)      Additional antiallergic mechanism apart from histamine blockade

d)     Does not impair psychomotor performance,

e)      No sleepiness, no complain of sedation

f)       Do not potentiate alcohol or BZD

Ex: Fexofenadine, Loratadine, Cetirizine

Rapidly absorbed, with peak plasma concentrations reached within 1 to 3 hours. Duration of action varies between 4 and 24. It undergoes first-pass and hepatic metabolism and eliminated as unchanged compounds in urine and feces.

Therapuetic uses:

1.      Allergic rhinitis but not vasomotor rhinitis

2.      Urticaria

3.      Dermographia

4.      Atopic eczema,

5.      Conjunctivitis.

Prostaglandins

Prostaglandins differs from each other in two ways: (1) in substituents of pentane ring and (2) in number of double bonds in side chains.

Alprostadil (PGE₁) may be used for its smooth muscle relaxing effects to maintain ductus arterosus patent in neonates awaiting cardiac surgery and in treatment of impotence.

Misoprostol, a PGE₁ derivative, is a cytoprotective prostaglandin used in preventing peptic ulcer and in combination with mifepristone for terminating early pregnancies. PGE₂ and PGF_2a are used in obstetrics to induce labor.

Latanoprost is topically active PGF_2alpha derivatives used in ophthalmology to treat open angle glaucoma.

Prostacyclin (PGI₂,) is powerful vasodilator and inhibitor of platelet aggregation. It is used clinically to treat pulmonary hypertension and portopulmonary hypertension.