AUTACOIDS AND THEIR ANTAGONISTS

AUTACOIDS AND THEIR ANTAGONISTS

Histamine and Antihistaminics: -

1. Chemistry

a. Histamine is a bioamine derived principally from dietary histidine, which is decarboxylated by L-histidine decarboxylase.

b. Antihistaminics (histamine antagonists) can be classified as H₁- or H₂- receptor antagonists.

(1) H₁- receptor antagonists, the classic antihistaminic agents, are chemically classified as ethylenediamines (e.g., pyrilamine), alkylamines (e.g., brompheniramine [Dimetapp], chlorpheniramine [Chlor-Trimeton] ), ethanolamines (e.g., diphenhydramine [Benadryl ], clemastine [Tavist] ), piperazines (e.g. , hydroxyzine [Atarax, Vistari l ], cetirizine [Zyrtec] ), phenothiazines (e.g., promethazine [Phenergan] ), dibenzocycloheptenes (cyproheptadine [Periactin] ), phthalazinones (azelastine [Optivar, Astelin]), and piperidines (e.g., azatadine [Optimine] , loratadine [Claritin], desloratadine [Clarinex] , and fexofenadine [Allegra] ). Cetirizine, azelastine, loratadine, desloratadine, and fexofenadine make up the second-generation antihistaminics, which are less sedating than the older, first -generation drugs, owing to their limited ability to cross the blood-brain barrier.

(2) H₂- receptor antagonists are heterocyclic congeners of histamine. These include cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid).

(3) Alternatives to the H2 - receptor antagonists include omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (AcipHex), pantoprazole (Protonix), and esomeprazole (Nexium); specific inhibitors of H+ /K+ -ATPase (proton pump inhibitors, or PPIs), the ultimate mediator of gastric acid secretion. Structurally, these agents are substituted benzimidazoles linked to a pyridine ring by a sulfinyl bridge, which is required for H+ /K+ -ATPase inhibition.

Pharmacology

a. Histamine has powerful pharmacological actions, mediated by two specific receptor types. A third histamine receptor has been identified. Its function has yet to be elucidated, but it is believed to act, at

least in part, as an autoreceptor.

(1) H₁- receptors mediate typical allergic and anaphylactic responses to histamine, such as bronchoconstriction, vasodilation, increased capillary permeability, and spasmodic contractions of gastrointestinal (GI) smooth muscle.

(2) H₂- receptors mediate other responses to histamine, such as increased secretion of gastric acid, pepsin, and Castle's factor (intrinsic factor).

b. H₁ - receptor antagonists competitively block H1 - receptors, thus limiting the histamine's effects on bronchial smooth muscle, capillaries, and GI smooth muscle. These antagonists also prevent histamine- induced pain and itching of the skin and mucous membranes.

c. H₂ - receptor antagonists competitively block H2 - receptors, thus limiting the effects of histamine on gastric secretions.

d. The PPIs irreversibly inhibit the proton pump H+ /K+ -ATPase by covalently binding to the protein.

B. Serotonin

1. Chemistry- a. Serotonin (5-hydroxyt ryptamine) is a bioamine that is synthesized from the amino acid tryptophan by a two-step enzymatic process catalyzed by tryptophan hydroxylase and L-amino acid decarboxylase.

b. Serotonin agonists

(1) 5-HT₁ - receptor agonists (i.e., sumatriptan [ Imitrex], rizatriptan [Maxalt], naratriptan [Amerge], zolmitriptan [Zomig], almotriptan [Axert], eletriptan [Relpax], and frovatriptan [Frova]) are indole derivatives structurally similar to serotonin.

(2) Tegaserod (Zelnorm), an indole derivative, acts as 5-HT₄ - receptor agonist.

(3) Ergot alkaloids (ergotamine [Ergomar]) have some activity as a serotonin agonist /partial agonist.

c. Serotonin antagonists

(1) Ergot alkaloids and derivatives with antagonist /partial agonist activity include ergonovine (Ergot rate), dihydroergotamine, methysergide, and bromocriptine (Parlodel).

(2) 5-HT₃ -antagonists may be either indole derivatives (ondansetron [Zofran]) or benzimidazoles (granisetron [Kytril]). Other drugs of the class include dolasetron (Anzemet), palonosetron (Aloxi) and alosetron (Lotronex).

Pharmacology

a. Serotonin exerts a wide range of effects via a family of receptors that includes at least seven types and several subtypes. Major physiological effects of serotonin include vasoconstriction (5-HT₂); platelet aggregation (5-HT₂); increased release of acetylcholine in the entericregion (5-HT₄); nausea/emesis (5-HT₃); and numerous behavioral actions that influence anxiety, depression, aggression, impulsivity, and appetite (5-HT₁, 5-HT₂, 5-HT₃). In addition, the 5-HT₁- receptor acts as an autoreceptor to inhibit presynaptic activity at both serotonergic and adrenergic neurones in the CNS. Furthermore, it directly contributes to vasculartone through vasoconstriction. Serotonin may also produce numerous other effects, including the opposite of those just stated, depending on the specific receptor that mediates the event.

b. Serotonin agonists

(1) 5-HT₁-agonists mimic the actions of serotonin at this receptor to decrease presynaptic neurotransmitter release. Direct vasoconstriction, decreased release of inflammatory and vasodilating substances (neurokinin A, substance P), and a directant inociceptive activities are thought to contribute to the efficacy of these drugs.

(2) Tegaserod act ivates the serotonergic receptor (5-HT₄), causing the release of acetylcholine, other neurotransmitters, and calcitonin gene- related peptide. These, in turn, increase gastric and intestinal motility and tone. In addition, direct actions on the gastrointestinal smooth muscle is thought to contributeit its effect, thus accounting for both the direct and indirect actions of tegaserod.

(3) Ergot alkaloids produce a wide range of pharmacological effects, including both agonistic and antagonistic activity at adrenergic, dopaminergic, and serotonergic receptors. Specif ic act ions dependent on drug and animal models.

c. Serotonin antagonists such as ondansetron and related drugs block the ionchannel coupled 5-HT₃ - receptor, thus inhibiting the ability of serotonin to cause nausea and/or emesis. This action appears to occur both locally at the GI tract and centrally in the area postrema. In addition, activation of peripheral 5-HT₃- receptors will increase pain, abdominal distention, and motor responses of the intestinal tract. Blockade of these actions, thus slowing GI motility, by alosetron is responsible for its usefulness in certain cases of irritable bowel syndrome (IBS).

C. Prostaglandins

1. Chemistry

a. Prostaglandins (PGs) are derivatives of prostanoic acid, a 20-carbon fatty acid containing a 5-carbon ring. In the body, prostaglandins are principally synthesized from arachidonic acid, which is formed from the membrane phospholipids by action of phospholipase A2. Specifically, prostaglandins are synthesized from arachidonic acid by the enzyme cyclooxygenase (COX), which exists as three isozymes: COX 1, 2, and 3. COX 1 appears to function constantly. Its role seems to be the daily synthesis of prostaglandins, which contribute to normal homeostasis, and includes protection of the gastric mucosa through the prostaglandins and hemostasis through the synthesis of thromboxane. COX-2 is expressed primarily in response to inflammation or injury, contributing to the inflammatory response. It is also important in normal (noninjury) regulation of cardiac and perhaps other functions. COX-3 is thought to be predominantly active within the CNS, contributing to normal thermoregulatory control and pain perception, through the synthesis of prostaglandins, centrally. Note that the products of cyclooxygenase are then converted into either prostaglandin by prostaglandin synthase or thromboxanes by thromboxane synthase. The thromboxanes differ from the prostaglandins mainly by the substitution of a tetrahydropyran ring structure for the pentanering found in prostaglandins. The only clinically relevant thromboxane currently identified is thromboxane A2 (TxA2), which causes platelet aggregation.

b. Classification of prostaglandins as prostaglandin A (PGA), prostaglandin B (PGB), prostaglandin E (PGE), and so for threlates to the presence or absence of keto or hydroxyl groups at positions 9 and 11. Subscripts relate to the number and position of double bonds in the aliphatic chains.

Pharmacology

a. Endogenous prostaglandins appear to affect numerous body functions. They are released in response to many chemical, bacterial, mechanical, and other insults; and they appear to contribute to the signs and symptoms of the inflammatory process, including pain and edema.

b. Physiological responses to prostaglandins include vasodilation in most vascular beds, although vasoconstriction can occur in isolated areas. PGI inhibits platelet aggregation and stimulates gastric release of bicarbonate and mucus, both of which serve to protect the gastric epithelium. The PGEs inhibit platelet aggregation, relax bronchial and GI smooth muscle, contract uterine smooth muscle, and inhibit gastic acid secretion. Alternatively, the PGDs and PGFs contract bronchial and GI smooth muscle. Prostaglandins also increase renal blood flow, promote diuresis, natriuresis, and kaliuresis; but paradoxically they increase renin secretion. They also possess diverse endocrine and metabolic effects.

D. Leukotrienes

1. Chemistry

a. Leukot rienes. The leukotrienes (LTs) are 20-carbon derivatives of the fatty acids that are formed via the enzymatic pathway catalyzed by lipoxygenase. Unlike the prostaglandins, they contain no ring structure and are covalently linked to two or three amino acids. The two important leukotrienes identified to date (LTC4 and LTD4) differ only by the presence of glutamine. The nomenclature of the leukotrienes is similar to that used for the prostaglandins.

b. Leukotriene antagonists

(1) Lipoxygenase inhibitors such as zileuton (Zyf lo) are benzothiophene derivatives.

(2) Leukotriene antagonists such as zafirlukast (Accolate) and montelukast (Singulair) represent a diverse chemical group that is peptidomimetic- like in its structure.

Pharmacology

a. Leukotrienes play a role in numerous physiological functions. They have been identified as the slow- reacting substance of anaphylaxis. Specific actions of the leukotrienes include the following:

(1) Heart

(a) Negative inotropy

(b) Smooth-muscle chemotaxis

(2) GI tract Neutrophil chemotaxis that has been correlated with inflammatory bowel disease

(3) Pulmonary. The actions of the leukotrienes within the pulmonary system appear to be major. These actions are the most important pharmacologically.

(a) Bronchoconst riction

(b) Increased permeability

(c) Increased mucus secretion

(4) Blood/ lymph. As noted previously, the leukotrienes act as chemotactic agents for neutrophils and eosinophils and act to modify lymphocyte proliferation and differentiation.

b. Leukot riene antagonists

(1) The lipoxygenase inhibitor zileuton prevents the synthesis of leukotrienes by inhibiting the enzyme responsible for their format ion namely lipoxygenase. This action prevents the formation of all leukotrienes, thus preventing their contribution to various inflammatory processes.

(2) The leukotriene antagonists zafirlukast and montelukast nonselectively and competitively inhibitthe endogenous leukotrienes at their various receptor sites. This action blocks the effects of histamine, most notably the bronchoconstriction and pulmonary edema associated with asthma and allergic reactions.