HISTAMINE, SEROTONIN, AND THEIR ANTAGONISTS

ELLIN FEBRINA

OBJECTIVES

List the major organ system effects of histamine and serotonin. Describe the pharmacology of the two generations and three subgroups of H1 antihistamines; list prototypical agents for each subgroup. Describe the pharmacology of the H2 antihistamines; identify the four members of this group.

OBJECTIVES

Describe the action, indication, and toxicity of sumatriptan. Describe one 5-HT2 and one 5-HT3 antagonist and their major applications.

CONCEPTS

Autacoids: Endogenous substances with complex physiologic and pathophysiologic functions; commonly interpreted to include: - histamine, - serotonin (5-hydroxytryptamine: 5-HT) - prostaglandins, and - vasoactive peptides.

CONCEPTS

Histamine and serotonin are synthesized in the body from amino acid precursors and then eliminated by amine oxidation; the pathways of synthesis and metabolism are very similar to those used for catecholamine synthesis and metabolism.

HISTAMINE

Histamine is formed from the amino acid histidine and is stored in high concentrations in vesicles in mast cells. Histamine is metabolized by the enzymes monoamine oxidase and diamine oxidase.

HISTAMINE

Excess production of histamine in the body (by, for example, systemic mastocytosis) can be detected by measurement of imidazoleacetic acid (its major metabolite) in the urine. Because it is released from mast cells in response to lgE-mediated (immediate) allergic reactions, this autacoid plays an important pathophysiologic role in seasonal rhinitis (hay fever), urticaria, and angioneurotic edema. Histamine also plays an important physiologic role in the control of acid secretion in the stomach and as a neurotransmitter.

HISTAMINE: Receptors and Effects

Receptors for histamine: - H1 and H2 Receptors (mediate most of the well defined peripheral actions) - H3 Receptor - H4 Receptor 1. H1 receptor: - Gq-coupled receptor - Important in smooth muscle effects, especially those caused by IgE-mediated responses. - IP 3 and DAG are the second messengers.

HISTAMINE: Receptors and Effects

HISTAMINE: Receptors and Effects

- Typical responses include bronchoconstriction and vasodilation [by release of nitric oxide, the major component of endothelium-derived relaxing factor (EDRF)]. - Capillary endothelium, in addition to releasing EDRF, also contracts, opening gaps in the permeability barrier and leading to the formation of local edema. - These effects are manifest in allergic reactions and in mastocytosis.

HISTAMINE: Receptors and Effects

2. H2 receptor: - Gs-coupled receptor - Mediates gastric acid secretion by parietal cells in the stomach - It also has a cardiac stimulant effect. - Reduce histamine release from mast cells (a negative feedback effect). - These actions are mediated by activation of adenylyl cyclase, which increases intracellular cAMP.

HISTAMINE: Receptors and Effects

3. H3 receptor: - This receptor appears to be involved mainly in presynaptic modulation of histaminergic neurotransmission in the central nervous system (CNS). - In the periphery, it appears to be a presynaptic heteroreceptor with modulatory effects on the release of other transmitters

H3 receptors function as autoreceptors on histaminergic neurons, much like presynaptic a2 receptors, inhibiting histamine release and modulating the release of other neurotransmitters. H3 antagonists promote wakefulness; conversely, H3 agonists promote sleep. H3 receptors appear to have high constitutive activity; thus histamine release may be tonically inhibited, and inverse agonists may reduce receptor activation and increase

H4 receptors are on immune active cells such as eosinophils and neutrophils, as well as in the gastrointestinal (GI) tract and CNS. Activation of H4 receptors on eosinophils induces a cellular shape change, chemotaxis, and up-regulation of adhesion molecules such as CD11b/CD18 and intercellular adhesion molecule (ICAM)-1, suggesting that the histamine released from mast cells acts at H4 receptors to recruit eosinophils. H4 antagonists may be useful inhibitors of

HISTAMINE: Clinical Use

Histamine has no therapeutic applications, but drugs that block histamine's effects are very important in clinical medicine.

HISTAMINE H1 ANTAGONISTS: Classification and Prototypes

Figure 16.1. Subgroups of histamine receptor blockers

HISTAMINE H1 ANTAGONISTS: Classification and Prototypes

- A wide variety of antihistaminic H1 blockers are available. - Two major subgroups or "generations" have been developed (Figure 16-1). - The older members of the first-generation, typified by diphenhydramine and doxylamine, are highly sedating agents with significant autonomic receptor- blocking effects.

- A newer subgroup of first-generation agents are less sedating and have much less autonomic effect. Chlorpheniramine and cycfizine may be considered prototypes. - The second-generation H1 blockers (typified by fexofenadine, loratadine, and cetirizine) are far less lipid-soluble than the first-generation agents and are mostly free of sedating and autonomic effects.

HISTAMINE H1 ANTAGONISTS: Classification and Prototypes

HISTAMINE H1 ANTAGONISTS: Classification and Prototypes

Because they have been developed for use in chronic conditions, all H1 blockers are active by the oral route. Most are metabolized extensively in the liver. Halflives of the older H1 blockers vary from 4 hours to 12 hours. Most newer agents (eg, fexofenadine, cetirizine, loratadine) have half-lives of 12-24 hours.

HISTAMINE H1 ANTAGONISTS: Mechanism and Effects

- H1 blockers are competitive pharmacologic antagonists at the H1 receptor; these drugs have no effect on histamine release from storage sites. - They are more effective if given before histamine release occurs. - Because their structure closely resembles that of muscarinic blockers and a-adrenoceptor blockers, many of the first-generation agents are potent pharmacologic antagonists at these autonomic receptors.

HISTAMINE H1 ANTAGONISTS: Mechanism and Effects

- A few also block serotonin receptors. - As noted above, most older first-generation agents are sedating, and some -not all- first generation agents have anti-motion sickness effects. - Many H1 blockers are potent local anesthetics. - H1-blocking drugs have negligible effects at H2 receptors.

HISTAMINE H1 ANTAGONISTS: Clinical Use

- H1 blockers have major applications in allergies of the immediate type (ie, those caused by antigens acting on IgE antibody-sensitized mast cells). - These conditions include hay fever and urticaria.

HISTAMINE H1 ANTAGONISTS: Clinical Use

- Diphenhydramine, dimenhydrinate, cyclizine, meclizine, and promethazine are used as antimotion sickness drugs. - Diphenhydramine is also used for management of chemotherapy-induced vomiting. - The drugs' adverse effects are sometimes exploited therapeutically, as in their use as hypnotics in institutions and in over-the-counter sleep aids.

HISTAMINE H1 ANTAGONISTS: Toxicity and Interactions

- Sedation is common, especially with diphenhydramine, doxylamine, and promethazine. - It is much less common with second-generation agents, which do not enter the CNS readily. - Antimuscarinic effects such as dry mouth and blurred vision occur with some first-generation drugs in some patients. - Alpha-blocking actions may cause orthostatic hypotension.

HISTAMINE H1 ANTAGONISTS: Toxicity and Interactions

Interactions occur between older antihistamines and other drugs with sedative effects, eg, benzodiazepines and alcohol. - Drugs that inhibit hepatic metabolism may result in dangerously high levels of certain antihistaminic drugs that are taken concurrently.

HISTAMINE H1 ANTAGONISTS: Toxicity and Interactions

- For example, azole antifungal drugs and certain other CYP3A4 inhibitors interfere with the metabolism of astemizole and terfenadine, two second-generation agents that have been withdrawn from the United States market. - Excessively high plasma concentrations of either antihistamine can precipitate lethal arrhythmias.

HISTAMINE H2 ANTAGONISTS: Classification and Prototypes

- Four H2 blockers are available: - Cimetidine is the prototype. - Ranitidine, famotidine, and nizatidine (differ only in being slightly less toxic than cimetidine). - Do not resemble H1 blockers structurally. - Orally active, with half-lives of 1-3 hours. - Relatively nontoxic, can be given in large doses, so that the duration of action of a single dose may be 12-24 hours.

HISTAMINE H2 ANTAGONISTS: Mechanism and Effects

Produce a surmountable pharmacologic blockade of histamine H2 receptors. Relatively selective and have no significant blocking actions at H2 or autonomic receptors. The only therapeutic effect of clinical importance is the reduction of gastric acid secretion, but this is a very useful action. Blockade of cardiovascular and mast cell H2 receptor-mediated effects can be demonstrated but has no clinical significance.

HISTAMINE H2 ANTAGONISTS: Clinical Use

- In acid-peptic disease, especially duodenal ulcer, these drugs reduce symptoms, accelerate healing, and prevent recurrences. - Acute ulcer is usually treated with two or more doses per day, while recurrence of the ulcer can often be prevented with a single bedtime dose. - H 2 blockers are also effective in accelerating healing and preventing recurrences of gastric peptic ulcers.

HISTAMINE H2 ANTAGONISTS: Clinical Use

- In Zollinger-Ellison syndrome, which is characterized by acid hypersecretion, severe recurrent peptic ulceration, gastrointestinal bleeding, and diarrhea, these drugs are very helpful (though large doses are required, and they are not as effective as proton pump inhibitors). Similarly, the H2 blockers have been used in gastroesophageal reflux disease (GERD), but they are not as effective as proton pump inhibitors.

HISTAMINE H2 ANTAGONISTS: Toxicity

- Cimetidine is a potent inhibitor of hepatic drug metabolizing enzymes and may also reduce hepatic blood flow. - Cimetidine also has significant antiandrogen effects in patients receiving high doses. - Ranitidine has a weaker inhibitory effect on hepatic drug metabolism; neither it nor the other H2 blockers appear to have endocrine effects.

HISTAMINE H3 AND H4 ANTAGONISTS

Although specific H3- and H4-receptor antagonists have been developed, no drugs have been approved for clinical use. Based on the functions of H3 receptors in the CNS, H3 antagonists have potential use in improving attention and learning, in stimulating arousal, and as antiepileptic agents.

HISTAMINE H3 AND H4 ANTAGONISTS

H4 antagonists are promising candidates to treat inflammatory conditions such as allergic rhinitis, asthma, and rheumatoid arthritis.

SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT) & RELATED AGONISTS

Serotonin is produced from tryptophan and stored in vesicles in the enterochromaffin cells of the gut and neurons of the CNS. After release, it is metabolized by monoamine oxidase. Excess production in the body can be detected by measuring its major metabolite. 5hydroxyindoleacetic acid (5-HIAA), in the urine.

SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT) & RELATED AGONISTS

Serotonin plays a physiologic role as a neurotransmitter in both the central nervous system and the enteric nervous system and perhaps has a role as a local hormone that modulates gastrointestinal activity. Serotonin is also stored (but synthesized to only a minimal extent) in platelets. In spite of the very large number of serotonin receptors (14 identified to date), the only serotonin agonists in clinical use act at 5-HT1D receptors. Serotonin antagonists in use or under investigation act at 5-HT 2 and 5-HT 3 receptors (Figure 16-2).

Figure 16-2. Subgroups of drugs acting at serotonin receptors and nerve endings.

SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT) & RELATED AGONISTS: Receptors and Effects

1. 5-HT 1 receptors: - 5-HT1receptors are most important in the brain and mediate synaptic inhibition via increased potassium conductance (Table 16-2). - Peripheral 5-HT1receptors mediate both excitatory and inhibitory effects in various smooth muscle tissues. - 5-HT 1 receptors are G i protein-coupled receptors.

SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT) & RELATED AGONISTS: Receptors and Effects

2. 5-HT 2 receptors: - 5-HT 2 receptors are important in both brain and peripheral tissues. - These receptors mediate synaptic excitation in the CNS and smooth muscle contraction (gut, bronchi, uterus, vessels) or dilation (vessels). - The mechanism involves (in different tissues) increased IP 3, decreased potassium conductance, and decreased cAMP. - This receptor probably mediates some of the vasodilation, diarrhea, and bronchoconstriction that occur as symptoms of carcinoid tumor, a neoplasm that releases serotonin and other substances.

SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT) & RELATED AGONISTS: Receptors and Effects

3. 5-HT 3 receptors: - 5-HT 3 receptors are found in the CNS, especially in the chemoreceptive area and vomiting center, and in peripheral sensory and enteric nerves. These receptors mediate excitation via a 5-HT-gated cation channel. - Antagonists acting at this receptor have proved to be extremely useful antiemetic drugs.

SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT) & RELATED AGONISTS: Clinical Use

Serotonin has no clinical applications.

SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT) & RELATED AGONISTS

Other Serotonin Agonists: 1. 5-HT1D agonists: Sumatriptan, a substituted indole compound, is the prototype. Naratriptan and rizatriptan are similar. They are effective in the treatment of acute migraine and cluster headache attacks, an observation that strengthens the association of serotonin abnormalities with these headache syndromes. - These drugs are active orally; sumatriptan is also available for parenteral administration. - Ergot alkaloids are partial agonists at 5-HT receptors.

SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT) & RELATED AGONISTS

2. Serotonin reuptake inhibitors: - A number of important antidepressant drugs act to

increase activity at serotonergic synapses by inhibiting the reuptake carrier for 5-HT.

SEROTONIN ANTAGONISTS:

Classification and Prototypes

Ketanserin is a 5-HT2 and alphaadrenecepter blocker. Phenoxybenzamine (an alphaadrenoceptor blocker) and cyproheptadine (an H 1 blocker) are also good 5-HT 2 blockers. Ondansetron, granisetron, dolasetron, and alosetron are 5-HT 3 blockers. The ergot alkaloids are partial agonists at 5-HT and other receptors.

SEROTONIN ANTAGONISTS:

Mechanisms and Effects

Ketanserin and cyproheptadine are competitive pharmacologic antagonists. Phenoxybenzamine is an irreversible blocker. Ketanserin, cyproheptadine, and phenoxybenzamine are weakly selective agents. In addition to inhibition of serotonin effects, they also have alpha-blocking effects (ketanserin, phenoxybenzamine) or H1 blocking effects (cyproheptadine). Ondansetron, granisetron, and dolasetron are selective 5-HT 3 receptor blockers and have a central antiemetic action in the area postrema of the medulla and also on peripheral sensory and enteric nerves.

SEROTONIN ANTAGONISTS:

Clinical Uses

Ketanserin has been studied as an antihypertensive drug. Ketanserin, cyproheptadine, and phenoxybenzamine may be of value (separately or in combination) in the treatment of carcinoid tumor, a neoplasm that secretes large amounts of serotonin (and peptides) and causes diarrhea, bronchoconstriction, and flushing. Ondansetron and its congeners are extremely useful in the central of vomiting associated with cancer chemotherapy and postoperative vomiting. Alosetron, another 5-HT 3 antagonist, was used in irritable bowel syndrome in women but has been withdrawn.

SEROTONIN ANTAGONISTS: Toxicity

Adverse effects of ketanserin are those of alpha blockade and H 1 blockade. The toxicities of ondansetron, granisetron, and dolasetron include diarrhea and headache. Dolasetron has been associated with QRS and QT c prolongation in the ECG and should not be used in patients with heart disease. Alosetron caused significant constipation in some patients.

DRUG LIST

The following drugs are important members of the group discussed in this chapter. Prototypes should be learned in detail; features of the major variants should be known well enough to distinguish them from the prototypes and from each other; the other significant agents should be recognized as belonging to a specific subclass.