Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids

Autacoids are endogenous molecules with powerful pharmacologic effects that do not fall into traditional autonomic groups. Histamine and serotonin (5-hydroxytryptamine; 5-HT) are the most important amine autacoids. The ergot alkaloids are a heterogeneous group of drugs (not autacoids) that interact with serotonin receptors, dopamine receptors, and α receptors. They are included in this chapter because of their effects on serotonin receptors and on smooth muscle. Peptide and eicosanoid autacoids are discussed in Chapters 17 and 18. Nitric oxide is discussed in Chapter 19.

Histamine is formed from the amino acidhistidine and is stored in high concentrations in vesicles in mast cells, enterochromaffin cells in the gut, some neurons, and a few other cell types. Histamine is metabolized by the enzymes monoamine oxidase and diamine oxidase. Excess production of histamine in the body (eg, in systemic mastocytosis) can be detected by measurement of its major metabolite, imidazole acetic acid, in the urine. Because it is released from mast cells in response to IgE-mediated (immediate) allergic reactions, this autacoid plays a pathophysiologic role in seasonal rhinitis (hay fever), urticaria, and angioneurotic edema. (The peptide bradykinin also plays an important role in angioneurotic edema, see Chapter 17.) Histamine also plays a physiologic role in the control of acid secretion in the stomach and as a neurotransmitter.

Receptors and Effects

Two receptors for histamine, H1 and H2, mediate most of the peripheral actions; 2 others (H3, H4) have also been identified (Table 16–1). The triple response, a classic demonstration of histamine effect, is mediated mainly by H1 and H2 receptors. This response involves a small red spot at the center of an intradermal injection of histamine surrounded by a red edematous wheal.

H1 Receptor

This Gq-coupled receptor is important in smooth muscle effects, especially those caused by IgE-mediated responses. Inositol trisphosphate (IP3) and diacylglycerol (DAG) are the second messengers. Typical responses include pain and itching in the skin, bronchoconstriction, and vasodilation, the latter caused by release of nitric oxide. Capillary endothelial cells, in addition to releasing nitric oxide (NO) and other vasodilating substances, also contract, opening gaps in the permeability barrier and leading to the formation of local edema. These effects occur in allergic reactions and in mastocytosis.

H2 Receptor

This Gs-coupled receptor mediates gastric acid secretion by parietal cells in the stomach. It also has a cardiac stimulant effect. A third action is to reduce histamine release from mast cells—a negative feedback effect. These actions are mediated by activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP).

H3 Receptor

This Gi-coupled receptor appears to be involved mainly in presynaptic modulation of histaminergic neurotransmission in the central nervous system (CNS). Food intake and body weight increase in H3-receptor knockout animals. In the periphery, it appears to be a presynaptic heteroreceptor with modulatory effects on the release of other transmitters (see Chapter 6).

H4 Receptor

The H4 receptor is located on leukocytes (especially eosinophils) and mast cells and is involved in chemotactic responses by these cells. Like H3, it is Gi coupled.

Clinical Use

Histamine has no therapeutic applications, but drugs that block its effects at H1 and at H2 receptors are very important in clinical medicine. No antagonists of H3 or H4 receptors are currently available for clinical use.

Classification and Prototypes

A wide variety of antihistaminic H1 blockers are available from several different chemical families. Two major subgroups or "generations" have been developed. The older members of the first-generation agents, typified by diphenhydramine, are highly sedating agents with significant autonomic receptor-blocking effects. A newer subgroup of first-generation agents is less sedating and has much less autonomic effect. Chlorpheniramine and cyclizine may be considered prototypes. The second-generation H1 blockers, typified by cetirizine, fexofenadine, and loratadine, are far less lipid soluble than the first-generation agents and have further reduced sedating and autonomic effects. All H1 blockers are active by the oral route. Several are promoted for topical use in the eye or nose. Most are metabolized extensively in the liver. Half-lives of the older H1 blockers vary from 4 to 12 h. Second-generation agents have half-lives of 12–24 h.

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 α-adrenoceptor blockers, many of the first-generation agents are potent pharmacologic antagonists at these autonomic receptors. A few also block serotonin receptors. As noted, 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.

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.

Diphenhydramine, dimenhydrinate, cyclizine, meclizine, and promethazine are used as anti-motion sickness drugs. Diphenhydramine is also used for management of chemotherapy-induced vomiting.

Adverse effects of the first-generation H1 blockers are sometimes exploited therapeutically (eg, in their use as hypnotics in over-the-counter sleep aids).

Toxicity and Interactions

Sedation is common, especially with diphenhydramine 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-adrenoceptor blockade, which is significant with phenothiazine derivatives such as promethazine, may cause orthostatic hypotension.

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. For example, azole antifungal drugs and certain other CYP3A4 inhibitors interfere with the metabolism of astemizole and terfenadine, 2 second-generation agents that have been withdrawn from the US market because high plasma concentrations of either antihistamine can precipitate lethal arrhythmias.

Classification and Prototypes

Four H2 blockers are available; cimetidine is the prototype. Ranitidine, famotidine, and nizatidine differ only in having fewer adverse effects than cimetidine. These drugs do not resemble H1 blockers structurally. They are orally active, with half-lives of 1–3 h. Because they are all relatively nontoxic, they can be given in large doses, so that the duration of action of a single dose may be 12–24 h. All four agents are available in oral over-the-counter formulations.

Mechanism and Effects

H2 antagonists produce a surmountable pharmacologic blockade of histamine H2 receptors. They are relatively selective and have no significant blocking actions at H1 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.

Clinical Use

In acid-peptic disease, especially duodenal ulcer, these drugs reduce nocturnal acid secretion, accelerate healing, and prevent recurrences. Acute ulcer is usually treated with 2 or more doses per day, whereas recurrence of ulcers can often be prevented with a single bedtime dose. H2 blockers are also effective in accelerating healing and preventing recurrences of gastric peptic ulcers. Intravenous H2 blockers are useful in preventing gastric erosions and hemorrhage that occur in stressed patients in intensive care units. In Zollinger-Ellison syndrome, which is associated with gastrinoma and characterized by acid hypersecretion, severe recurrent peptic ulceration, gastrointestinal bleeding, and diarrhea, these drugs are helpful, but very large doses are required; proton pump inhibitors are preferred. Similarly, the H2 blockers have been used in gastroesophageal reflux disease (GERD), but they are not as effective as proton pump inhibitors (see Chapter 60).

Toxicity

Cimetidine is a potent inhibitor of hepatic drug-metabolizing enzymes (see Chapter 4) 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 any endocrine effects.

(See Chapters 8 and 10)

An elderly dental patient was given promethazine intravenously to reduce anxiety before undergoing an extraction in the dental office. Promethazine is an older first-generation antihistamine. Predict the CNS and autonomic effects of this drug when given intravenously. The Skill Keeper Answer appears at the end of the chapter.

Serotonin is produced from tryptophan and stored in vesicles in the enterochromaffin cells of the gut and neurons of the CNS and enteric nervous system. After release, it is metabolized by monoamine oxidase. Excess production in the body (eg, in carcinoid syndrome) can be detected by measuring its major metabolite, 5-hydroxyindole acetic acid (5-HIAA), in the urine. Serotonin plays a physiologic role as a neurotransmitter in both the CNS and the enteric nervous system and may have 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), most of the serotonin agonists in clinical use act at 5-HT1D receptors. Serotonin antagonists in use or under investigation act at 5-HT2 and 5-HT3 receptors (see drug overview figure at the beginning of the chapter).

Receptors and Effects

5-HT1 Receptors

5-HT1 receptors are most important in the brain and mediate synaptic inhibition via increased potassium conductance (Table 16–1). Peripheral 5-HT1 receptors mediate both excitatory and inhibitory effects in various smooth muscle tissues. 5-HT1 receptors are Gi-protein-coupled.

5-HT2 Receptors

5-HT2 receptors are important in both brain and peripheral tissues. These receptors mediate synaptic excitation in the CNS and smooth muscle contraction (gut, bronchi, uterus, some vessels) or relaxation (other vessels). Several mechanisms are involved, including (in different tissues) increased IP3, 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.

5-HT3 Receptors

5-HT3 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 are extremely useful antiemetic drugs.

5-HT4 Receptors

5-HT4 receptors are found in the gastrointestinal tract and play an important role in intestinal motility.

Clinical Uses

Serotonin has no clinical applications, but other more selective agonists are useful.

5-HT1D Agonists

Sumatriptan is the prototype. Naratriptan and other "-triptans" are similar to sumatriptan (see Drug Summary Table). They are the first-line treatment for 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 nasal and parenteral administration. Ergot alkaloids, discussed later, are partial agonists at some 5-HT receptors.

5-HT4 Partial Agonist

Tegaserod is a newer drug that acts as an agonist in the colon. It was approved and briefly marketed for use in chronic constipation, but because of cardiovascular toxicity, its use is now restricted.

Selective Serotonin Reuptake Inhibitors (SSRI)

A number of important antidepressant drugs act to increase activity at central serotonergic synapses by inhibiting the serotonin reuptake transporter, SERT. These drugs are discussed in Chapter 30. Dexfenfluramine (now withdrawn because of cardiotoxicity) was a reuptake inhibitor used exclusively for its appetite-reducing effect. Dexfenfluramine was combined with phentermine, an amphetamine-like anorexiant, in a weight-loss product known as "fen-phen." Because of toxicity, this combination product is also banned.

Hyperpyrexic Syndromes

Serotonin and drugs with 5-HT agonist effects are sometimes associated with drug reactions with high fever, skeletal muscle effects, and cardiovascular abnormalities that can be life-threatening. These important syndromes are summarized in Table 16–2.

Classification and Prototypes

Ketanserin, phenoxybenzamine, and cyproheptadine are effective 5-HT2 blockers. Ondansetron, granisetron, dolasetron, and alosetron are 5-HT3 blockers. The ergotalkaloids are partial agonists (and therefore have some antagonist effects) at 5-HT and other receptors (see later discussion).

Mechanisms and Effects

Ketanserin and cyproheptadine are competitive pharmacologic 5-HT2 antagonists. Phenoxybenzamine is an irreversible blocker at this receptor.

Ketanserin, cyproheptadine, and phenoxybenzamine are poorly selective agents. In addition to inhibition of serotonin effects, other actions include α-blockade (ketanserin, phenoxybenzamine) or H1-blockade (cyproheptadine).

Ondansetron, granisetron, and dolasetron are selective 5-HT3 receptor blockers and have important antiemetic actions in the area postrema of the medulla and also on peripheral sensory and enteric nerves. Although it acts at the same receptor, alosetron appears to lack these antiemetic effects.

Clinical Uses

Ketanserin is used as an antihypertensive drug outside the United States. 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 control of vomiting associated with cancer chemotherapy and postoperative vomiting. Alosetron is used in the treatment of women with irritable bowel syndrome associated with diarrhea.

Toxicity

Adverse effects of ketanserin are those of α blockade and H1 blockade. The toxicities of ondansetron, granisetron, and dolasetron include diarrhea and headache. Dolasetron has been associated with QRS and QTc prolongation in the ECG and should not be used in patients with heart disease. Alosetron causes significant constipation in some patients and has been associated with fatal bowel complications.

These complex molecules are produced by a fungus found in wet or spoiled grain. They are responsible for the epidemics of "St. Anthony's fire" (ergotism) described during the Middle Ages and recurring to the present time. There are at least 20 naturally occurring members of the family, but only a few of these and a handful of semisynthetic derivatives are used as therapeutic agents. Most ergot alkaloids are partial agonists at α adrenoceptors and 5-HT receptors, and some are potent agonists at dopamine receptors.

Classification and Effects

The ergot alkaloids may be divided into 3 major subgroups on the basis of the organ or tissue in which they have their primary effects. The receptor effects of the ergot alkaloids are summarized in Table 16–3 and are most marked in the following tissues:

Vessels

Ergot alkaloids can produce marked and prolonged α-receptor-mediated vasoconstriction. Ergotamine is the prototype. An overdose can cause ischemia and gangrene of the limbs or bowel. Because they are partial agonists, the drugs may also block the α-agonist effects of sympathomimetics, and ergotamine can cause epinephrine reversal.

Uterus

Ergot alkaloids produce powerful contraction in this tissue, especially near term. Ergonovine is the prototype. In pregnancy, the uterine contraction is sufficient to cause abortion or miscarriage. Earlier in pregnancy (and in the nonpregnant uterus) much higher doses of ergot alkaloids are needed to cause contraction.

Brain

Hallucinations may be prominent with the naturally occurring ergots and with lysergic acid diethylamide(LSD), a semisynthetic prototypical hallucinogenic ergot derivative, but are uncommon with the therapeutic ergot derivatives. Although LSD is a potent 5-HT2 blocker in peripheral tissues, its actions in the CNS are thought to be due to agonist actions at dopamine receptors. In the pituitary, some ergot alkaloids are potent dopamine-like agonists and inhibit prolactin secretion. Bromocriptine and pergolide are among the most potent semisynthetic ergot derivatives. They act as dopamine D2 receptors in the pituitary and in the basal ganglia (see Chapter 28).

Clinical Uses

Migraine

Ergotamine has been a mainstay of treatment of acute attacks and is still used in combination with caffeine. Methysergide, dihydroergonovine, and ergonovine have been used for prophylaxis, but methysergide is no longer available in the United States. The triptan derivatives are now considered preferable to the ergots because of lower toxicity.

Obstetric Bleeding

Ergonovine and ergotamine are effective agents for the reduction of postpartum bleeding. They produce a powerful and long-lasting contraction that reduces bleeding but must not be given before delivery of the placenta.

Hyperprolactinemia and Parkinsonism

Bromocriptine and pergolide have been used to reduce prolactin secretion (dopamine is the physiologic prolactin release inhibitor; Chapter 37). Bromocriptine also appears to reduce the size of pituitary tumors of the prolactin-secreting cells. Both drugs have been used in the treatment of Parkinson's disease (see Chapter 28).

Toxicity

The toxic effects of ergot alkaloids are quite important, both from a public health standpoint (epidemics of ergotism from spoiled grain) and from the toxicity resulting from overdose or abuse by individuals. Intoxication of grazing animals is sometimes reported by farmers and veterinarians.

Vascular Effects

Severe prolonged vasoconstriction can result in ischemia and gangrene. The most consistently effective antidote is nitroprusside. When used for long periods, ergot derivatives may produce an unusual hyperplasia of connective tissue. This fibroplasia may be retroperitoneal, retropleural, or subendocardial and can cause hydronephrosis or cardiac valvular and conduction system malfunction. Similar lesions are found in some patients with carcinoid, suggesting that this action is probably mediated by agonist effects at serotonin receptors.

Gastrointestinal Effects

Ergot alkaloids cause gastrointestinal upset (nausea, vomiting, diarrhea) in many persons.

Uterine Effects

Marked uterine contractions may be produced. The uterus becomes progressively more sensitive to ergot alkaloids during pregnancy. Although abortion resulting from the use of ergot for migraine is rare, most obstetricians recommend avoidance or very conservative use of these drugs as pregnancy progresses.

CNS Effects

Hallucinations resembling psychosis are common with LSD but less so with the other ergot alkaloids. Methysergide was occasionally used in the past as an LSD substitute by users of "recreational" drugs.

(See Chapters 8 and 10)

Promethazine very effectively alleviated the anxiety of this elderly woman. However, when she attempted to get out of the dental chair after the procedure, she experienced severe orthostatic hypotension and fainted. In the horizontal position on the floor and later on a couch, she rapidly regained consciousness. Supine blood pressure was low normal, and heart rate was elevated. When she sat up, blood pressure dropped and heart rate increased. Promethazine and several other first-generation H1 antihistamines are effective α (and M3) blockers (Chapters 8 and 10). After 30 min supine, the patient was able to stand without fainting and experienced only a slight tachycardia. Older antihistaminic agents readily enter the CNS, causing sedation. This patient felt somewhat sleepy for 2 h but had no further signs or symptoms. If she had glaucoma, she might be at risk for an acute angle-closure episode, with markedly increased intraocular pressure as a result of the antimuscarinic action. An elderly man with prostatic hyperplasia might experience urinary retention.

When you complete this chapter, you should be able to:

• □ List the major organ system effects of histamine and serotonin.
• □ Describe the pharmacology of the 2 generations and 3 subgroups of H1 antihistamines; list prototypical agents for each subgroup.
• □ Describe the pharmacology of the H2 antihistamines; name 2 members of this group.
• □ Describe the action and indication for the use of sumatriptan.
• □ Describe one 5-HT2 and one 5-HT3 antagonist and their major applications.
• □ List the major organ system effects of the ergot alkaloids.
• □ Describe the major clinical applications and toxicities of the ergot drugs.