Before the identification of 5-hydroxytryptamine (5-HT), it was known that when blood is allowed to clot, a vasoconstrictor (tonic) substance is released from the clot into the serum. This substance was called serotonin. Independent studies established the existence of a smooth muscle stimulant in intestinal mucosa. This was called enteramine. The synthesis of 5-hydroxytryptamine in 1951 led to the identification of serotonin and enteramine as the same metabolite of 5-hydroxytryptophan.
Serotonin is an important neurotransmitter, a local hormone in the gut, a component of the platelet clotting process, and is thought to play a role in migraine headache and several other clinical conditions, including carcinoid syndrome. This syndrome is an unusual manifestation of carcinoid tumor, a neoplasm of enterochromaffin cells. In patients whose tumor is not surgically resectable, a serotonin antagonist may constitute a useful treatment.
BASIC PHARMACOLOGY OF SEROTONIN
Chemistry & Pharmacokinetics
Like histamine, serotonin is widely distributed in nature, being found in plant and animal tissues, venoms, and stings. It is synthesized in biologic systems from the amino acid l-tryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid (Figure 16–2). Hydroxylation at C5 by tryptophan hydroxylase-1 is the rate-limiting step and can be blocked by p-chlorophenylalanine (PCPA; fenclonine) and by p-chloroamphetamine. These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome but are too toxic for general clinical use. Telotristat ethyl, an orally active hydroxylase inhibitor, has been approved for the treatment of diarrhea due to carcinoid tumor.
Synthesis of serotonin and melatonin from l-tryptophan.
After synthesis, the free amine is stored in vesicles or is rapidly inactivated, usually by oxidation by monoamine oxidase (MAO). In the pineal gland, serotonin serves as a precursor of melatonin, a melanocyte-stimulating hormone that has complex effects in several tissues. In mammals (including humans), over 90% of the serotonin in the body is found in enterochromaffin cells in the gastrointestinal tract. In the blood, serotonin is found in platelets, which are able to concentrate the amine by means of an active serotonin transporter mechanism (SERT) similar to that in the membrane of serotonergic nerve endings. Once transported into the platelet or nerve ending, 5-HT is concentrated in vesicles by a vesicle-associated transporter (VAT) that is blocked by reserpine. Serotonin is also found in the raphe nuclei of the brainstem, which contain cell bodies of serotonergic neurons that synthesize, store, and release serotonin as a transmitter. Stored serotonin can be depleted by reserpine in much the same manner as this drug depletes catecholamines from vesicles in adrenergic nerves and the adrenal medulla (see Chapter 6).
Brain serotonergic neurons are involved in numerous diffuse functions such as mood, sleep, appetite, and temperature regulation, as well as the perception of pain, the regulation of blood pressure, and vomiting (see Chapter 21). Serotonin is clearly involved in psychiatric depression (see Chapter 30) and also appears to be involved in conditions such as anxiety and migraine. Serotonergic neurons are found in the enteric nervous system of the gastrointestinal tract and around blood vessels. In rodents (but not in humans), serotonin is also found in mast cells.
The function of serotonin in enterochromaffin cells is not fully understood. These cells synthesize serotonin, store the amine in a complex with adenosine triphosphate (ATP) and other substances in granules, and release serotonin in response to mechanical and neuronal stimuli. This serotonin interacts in a paracrine fashion with several different 5-HT receptors in the gut (see Chapter 62). Some of the released serotonin diffuses into blood vessels and is taken up and stored in platelets.
Serotonin is metabolized by MAO, and the intermediate product, 5-hydroxyindoleacetaldehyde, is further oxidized by aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA). In humans consuming a normal diet, the excretion of 5-HIAA is a measure of serotonin synthesis. Therefore, the 24-hour excretion of 5-HIAA can be used as a diagnostic test for tumors that synthesize excessive quantities of serotonin, especially carcinoid tumor. A few foods (eg, bananas) contain large amounts of serotonin or its precursors and must be prohibited during such diagnostic tests.
Serotonin exerts many actions and, like histamine, displays many species differences, making generalizations difficult. The actions of serotonin are mediated through a remarkably large number of cell membrane receptors. The serotonin receptors that have been characterized thus far are listed in Table 16–3. Seven families of 5-HT-receptor subtypes (those given numeric subscripts 1 through 7) have been identified, six involving G protein-coupled receptors of the usual seven-transmembrane serpentine type and one a ligand-gated ion channel. The latter (5-HT3) receptor is a member of the nicotinic family of Na+/K+ channel proteins.
TABLE 16–3Serotonin receptor subtypes currently recognized. (See also Chapter 21.) ||Download (.pdf) TABLE 16–3 Serotonin receptor subtypes currently recognized. (See also Chapter 21.)
|Receptor Subtype ||Distribution ||Postreceptor Mechanism ||Partially Selective Agonists ||Partially Selective Antagonists |
|5-HT1A ||Raphe nuclei, hippocampus ||Gi, ↓ cAMP ||8-OH-DPAT,1 repinotan ||WAY1006351 |
|5-HT1B ||Substantia nigra, globus pallidus, basal ganglia ||Gi, ↓ cAMP ||Sumatriptan, L6942471 || |
|5-HT1D ||Brain ||Gi, ↓ cAMP ||Sumatriptan, eletriptan || |
|5-HT1E ||Cortex, putamen ||Gi, ↓ cAMP || || |
|5-HT1F ||Cortex, hippocampus ||Gi, ↓ cAMP ||LY33448641 || |
|5-HT1P ||Enteric nervous system ||Go, slow EPSP ||5-Hydroxyindalpine ||Renzapride |
|5-HT2A ||Platelets, smooth muscle, cerebral cortex ||Gq, ↑ IP3 ||α-Methyl-5-HT, DOI1 ||Ketanserin |
|5-HT2B ||Stomach fundus ||Gq, ↑ IP3 ||α-Methyl-5-HT, DOI1 ||RS1274451 |
|5-HT2C ||Choroid, hippocampus, substantia nigra ||Gq, ↑ IP3 ||α-Methyl-5-HT, DOI,1 lorcaserin ||Mesulergine |
|5-HT3 ||Area postrema, sensory and enteric nerves ||Receptor is an Na+/K+ ion channel ||2-Methyl-5-HT, m-chlorophenylbiguanide ||Granisetron, ondansetron, others |
|5-HT4 ||CNS and myenteric neurons, smooth muscle ||Gs, ↑ cAMP ||BIMU8,1 renzapride, metoclopramide ||GR1138081 |
|5-HT5A,B ||Brain ||↓ cAMP || || |
|5-HT6,7 ||Brain ||Gs, ↑ cAMP || ||Clozapine (5-HT7) |
B. Tissue and Organ System Effects
1. Nervous system—Serotonin is present in a variety of sites in the brain. Its role as a neurotransmitter and its relation to the actions of drugs acting in the central nervous system are discussed in Chapters 21 and 30. Serotonin is also a precursor of melatonin in the pineal gland (Figure 16–2; see Box: Melatonin Pharmacology). Repinotan, a 5-HT1A agonist currently in clinical trials, appears to have some antinociceptive action at higher doses while reversing opioid-induced respiratory depression.
Melatonin is N-acetyl-5-methoxytryptamine (Figure 16–2), a simple methoxylated and N-acetylated product of serotonin found in the pineal gland. It is produced and released primarily at night and has long been suspected of playing a role in diurnal cycles of animals and the sleep-wake behavior of humans. Melatonin receptors have been characterized in the central nervous system and several peripheral tissues. In the brain, MT1 and MT2 receptors are found in membranes of neurons in the suprachiasmatic nucleus of the hypothalamus, an area associated—from lesioning experiments—with circadian rhythm. MT1 and MT2 are seven-transmembrane Gi protein-coupled receptors. The result of receptor binding is inhibition of adenylyl cyclase. A third receptor, MT3, is an enzyme; binding to this site has a poorly defined physiologic role, possibly related to intraocular pressure. Activation of the MT1 receptor results in sleepiness, whereas the MT2 receptor may be related to the light-dark synchronization of the biologic circadian clock. Melatonin has also been implicated in energy metabolism and obesity, and administration of the agent reduces body weight in certain animal models. However, its role in these processes is poorly understood, and there is no evidence that melatonin itself is of any value in obesity in humans. Other studies suggest that melatonin has antiapoptotic effects in experimental models. Recent research implicates melatonin receptors in depressive disorders. Insomnia associated with autism spectrum disorder may respond to melatonin.
Melatonin is promoted commercially as a sleep aid by the food supplement industry (see Chapter 64). There is an extensive literature supporting its use in ameliorating jet lag. It is used in oral doses of 0.5–5 mg, usually administered at the destination bedtime. Ramelteon is a selective MT1 and MT2 agonist that is approved for the medical treatment of insomnia. This drug has no addiction liability (it is not a controlled substance), and it appears to be distinctly more efficacious than melatonin (but less efficacious than benzodiazepines) as a hypnotic. It is metabolized by P450 enzymes and should not be used in individuals taking CYP1A2 inhibitors. It has a half-life of 1–3 hours and an active metabolite with a half-life of up to 5 hours. Ramelteon may increase prolactin levels. Tasimelteon is a newer MT1 and MT2 agonist that is approved for non-24-hour sleep-wake disorder. Agomelatine, an MT1 and MT2 agonist and a 5-HT2C antagonist, is approved in Europe for use in major depressive disorder.
5-HT3 receptors in the gastrointestinal tract and in the vomiting center of the medulla participate in the vomiting reflex (see Chapter 62). They are particularly important in vomiting caused by chemical triggers such as cancer chemotherapy drugs. 5-HT1P and 5-HT4 receptors also play important roles in enteric nervous system function.
Like histamine, serotonin is a potent stimulant of pain and itch sensory nerve endings and is responsible for some of the symptoms caused by insect and plant stings. In addition, serotonin is a powerful activator of chemosensitive endings located in the coronary vascular bed. Activation of 5-HT3 receptors on these afferent vagal nerve endings is associated with the chemoreceptor reflex (also known as the Bezold-Jarisch reflex). The reflex response consists of marked bradycardia and hypotension, and its physiologic role is uncertain. The bradycardia is mediated by vagal outflow to the heart and can be blocked by atropine. The hypotension is a consequence of the decrease in cardiac output that results from bradycardia. A variety of other agents can activate the chemoreceptor reflex. These include nicotinic cholinoceptor agonists and some cardiac glycosides, eg, ouabain.
Although serotonergic neurons are not found below the site of injury to the adult spinal cord, constitutive activity of 5-HT receptors may play a role following such a lesion—administration of 5-HT2 blockers appears to reduce skeletal muscle spasm following this type of injury.
2. Respiratory system—Serotonin has a small direct stimulant effect on bronchiolar smooth muscle in normal humans, probably via 5-HT2A receptors. It also appears to facilitate acetylcholine release from bronchial vagal nerve endings. In patients with carcinoid syndrome, episodes of bronchoconstriction occur in response to elevated levels of the amine or peptides released from the tumor. Serotonin may also cause hyperventilation as a result of the chemoreceptor reflex or stimulation of bronchial sensory nerve endings.
3. Cardiovascular system—Serotonin directly causes the contraction of vascular smooth muscle, mainly through 5-HT2 receptors. In humans, serotonin is a powerful vasoconstrictor except in skeletal muscle and the heart, where it dilates blood vessels.
At least part of the 5-HT-induced vasodilation requires the presence of vascular endothelial cells. When the endothelium is damaged, coronary vessels are constricted by 5-HT. As noted previously, serotonin can also elicit reflex bradycardia by activation of 5-HT3 receptors on chemoreceptor nerve endings. A triphasic blood pressure response is often seen following injection of serotonin in experimental animals. Initially, there is a decrease in heart rate, cardiac output, and blood pressure caused by the chemoreceptor response. After this decrease, blood pressure increases as a result of vasoconstriction. The third phase is again a decrease in blood pressure attributed to vasodilation in vessels supplying skeletal muscle. In contrast, pulmonary and renal vessels seem very sensitive to the vasoconstrictor action of serotonin.
Studies in knockout mice suggest that 5-HT, acting on 5-HT1A, 5-HT2, and 5-HT4 receptors, is needed for normal cardiac development in the fetus. On the other hand, chronic exposure of adults to 5-HT2B agonists is associated with valvulopathy and adult mice lacking the 5-HT2B receptor gene are protected from cardiac hypertrophy. Preliminary studies suggest that 5-HT2B antagonists can prevent development of pulmonary hypertension in animal models.
Serotonin also constricts veins, and venoconstriction with increased capillary filling appears to be responsible for the flush that is observed after serotonin administration or release from a carcinoid tumor. Serotonin has small direct positive chronotropic and inotropic effects on the heart, which are probably of no clinical significance. However, prolonged elevation of the blood level of serotonin (which occurs in carcinoid syndrome) is associated with pathologic alterations in the endocardium (subendocardial fibroplasia), which may result in valvular or electrical malfunction.
Serotonin causes blood platelets to aggregate by activating 5-HT2 receptors. This response, in contrast to aggregation induced during normal clot formation, is not accompanied by the release of serotonin stored in the platelets. The physiologic role of this effect is unclear.
4. Gastrointestinal tract—Serotonin is a powerful stimulant of gastrointestinal smooth muscle, increasing tone and facilitating peristalsis. This action is caused by the direct action of serotonin on 5-HT2 smooth muscle receptors plus a stimulating action on ganglion cells located in the enteric nervous system (see Chapter 6). 5-HT1A and 5-HT7 receptors may also be involved. Activation of 5-HT4 receptors in the enteric nervous system causes increased acetylcholine release and thereby mediates a motility-enhancing or “prokinetic” effect of selective serotonin agonists such as cisapride. These agents are useful in several gastrointestinal disorders (see Chapter 62). Overproduction of serotonin (and other substances) in carcinoid tumor is associated with severe diarrhea. Serotonin has little effect on gastrointestinal secretions, and what effects it has are generally inhibitory.
5. Skeletal muscle and the eye—5-HT2 receptors are present on skeletal muscle membranes, but their physiologic role is not understood. As discussed in the box, serotonin syndrome is associated with skeletal muscle contractions and precipitated when MAO inhibitors are given with serotonin agonists, especially antidepressants of the selective serotonin reuptake inhibitor class (SSRIs; see Chapter 30). Although the hyperthermia of serotonin syndrome results from excessive muscle contraction, serotonin syndrome is probably caused by a central nervous system effect of these drugs (Table 16–4 and Box: Serotonin Syndrome and Similar Syndromes).
Serotonin Syndrome and Similar Syndromes
Excess synaptic serotonin causes a serious, potentially fatal syndrome that is diagnosed on the basis of a history of administration of a serotonergic drug within recent weeks and physical findings. It has some characteristics in common with neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH), but its pathophysiology and management are quite different (Table 16–4).
As suggested by the drugs that precipitate it, serotonin syndrome occurs when overdose with a single drug, or concurrent use of several drugs, results in excess serotonergic activity in the central nervous system. It is predictable and not idiosyncratic, but milder forms may easily be misdiagnosed. In experimental animal models, many of the signs of the syndrome can be reversed by administration of 5-HT2 antagonists; however, other 5-HT receptors may be involved as well. Dantrolene is of no value, unlike the treatment of MH.
NMS is idiosyncratic rather than predictable and appears to be associated with hypersensitivity to the parkinsonism-inducing effects of D2-blocking antipsychotics in certain individuals. MH is associated with a genetic defect in the RyR1 calcium channel of skeletal muscle sarcoplasmic reticulum that permits uncontrolled calcium release from the sarcoplasmic reticulum when precipitating drugs are given (see Chapter 27).
Studies in animal models of glaucoma indicate that 5-HT2A agonists reduce intraocular pressure. This action can be blocked by ketanserin and similar 5-HT2 antagonists.
TABLE 16–4Characteristics of serotonin syndrome and other hyperthermic syndromes. ||Download (.pdf) TABLE 16–4 Characteristics of serotonin syndrome and other hyperthermic syndromes.
|Syndrome ||Precipitating Drugs ||Clinical Presentation ||Therapy1 |
|Serotonin syndrome ||SSRIs, second-generation antidepressants, MAOIs, linezolid, tramadol, meperidine, fentanyl, ondansetron, sumatriptan, MDMA, LSD, St. John’s wort, ginseng ||Hypertension, hyperreflexia, tremor, clonus, hyperthermia, hyperactive bowel sounds, diarrhea, mydriasis, agitation, coma; onset within hours ||Sedation (benzodiazepines), paralysis, intubation, and ventilation; consider 5-HT2 block with cyproheptadine or chlorpromazine |
|Neuroleptic malignant syndrome ||D2-blocking antipsychotics ||Acute severe parkinsonism; hypertension, hyperthermia, normal or reduced bowel sounds; onset over 1–3 days ||Diphenhydramine (parenteral), cooling if temperature is very high, sedation with benzodiazepines |
|Malignant hyperthermia ||Volatile anesthetics, succinylcholine ||Hyperthermia, muscle rigidity, hypertension, tachycardia; onset within minutes ||Dantrolene, cooling |
CLINICAL PHARMACOLOGY OF SEROTONIN
Serotonin has no clinical applications as a drug. However, several receptor subtype-selective agonists have proved to be of value. Buspirone, a 5-HT1A agonist, has received attention as an effective nonbenzodiazepine anxiolytic (see Chapter 22). Appetite suppression appears to be associated with agonist action at 5-HT2C receptors in the central nervous system, and dexfenfluramine, a selective 5-HT agonist, was widely used as an appetite suppressant but was withdrawn because of cardiac valvulopathy. Lorcaserin, a 5-HT2C agonist, is approved by the FDA for use as a weight-loss medication (see Box: Treatment of Obesity).
Treatment of Obesity
It is said that much of the world is experiencing an “epidemic of obesity.” This statement is based on statistics showing that in the USA and many other countries, 30–40% of the population is above optimal weight, and that the excess weight (especially abdominal fat) is often associated with the metabolic syndrome and increased risks of cardiovascular disease and diabetes. Since eating behavior is an expression of endocrine, neurophysiologic, and psychological processes, prevention and treatment of obesity are challenging. There is considerable scientific and financial interest in developing pharmacologic therapy for the condition.
Although obesity can be defined as excess adipose tissue, it is currently quantitated by means of the body mass index (BMI), calculated from BMI = weight (in kilograms)/height2 (in meters). Using this measure, the range of normal BMI is defined as 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; and morbidly obese (ie, at very high risk), ≥40. (Underweight persons, ie, those with a BMI < 18, also have an increased [but smaller] risk of health problems.) Some extremely muscular individuals may have a BMI higher than 25 and no excess fat; however, the BMI scale generally correlates with the degree of obesity and with risk. A second metric, which may be an even better predictor of cardiovascular risk, is the ratio of waist measurement to body height; cardiovascular risk is lower if this ratio is less than 0.5. Experts consider drug therapy to be justified in patients with increased risk factors and a BMI ≥ 27 and in those without comorbidities but with a BMI ≥ 30.
Although the cause of obesity can be simply stated as energy intake (dietary calories) that exceeds energy output (resting metabolism plus exercise), the actual physiology of weight control is extremely complex, and the pathophysiology of obesity is still poorly understood. Many hormones and neuronal mechanisms regulate intake (appetite, satiety), processing (absorption, conversion to fat, glycogen, etc), and output (thermogenesis, muscle work). The fact that a large number of hormones reduce appetite might appear to offer many targets for weight-reducing drug therapy, but despite intensive research, no available pharmacologic therapy has succeeded in maintaining a weight loss of over 10% for 1 year. Furthermore, the social and psychological aspects of eating are powerful influences that are independent of or only partially dependent on the physiologic control mechanisms. In contrast, bariatric (weight-reducing) surgery readily achieves a sustained weight loss of 10–40%. Furthermore, surgery that bypasses the stomach and upper small intestine (but not simple restrictive banding) rapidly reverses some aspects of the metabolic syndrome even before significant loss of weight. Even a 5–10% loss of weight is associated with a reduction in blood pressure and improved glycemic control. Gastrointestinal flora also influence metabolic efficiency, and research in mice suggests that altering the microbiome can lead to weight gain or loss.
Until approximately 15 years ago, the most popular and successful appetite suppressants were the nonselective 5-HT2 agonists fenfluramine and dexfenfluramine. Combined with phentermine as Fen-Phen and Dex-Phen, they were moderately effective. However, these 5-HT2 agonists were found to cause pulmonary hypertension and cardiac valve defects and were withdrawn.
Older drugs still available in the USA and some other countries include phenylpropanolamine, benzphetamine, amphetamine, methamphetamine, phentermine, diethylpropion, mazindol, and phendimetrazine. These drugs are all amphetamine mimics and are central nervous system appetite suppressants; they are generally helpful only during the first few weeks of therapy. Their toxicity is significant and includes hypertension (with a risk of cerebral hemorrhage) and addiction liability.
Liraglutide, lorcaserin, orlistat, and phentermine are the only single-agent drugs currently approved in the USA for the treatment of obesity. In addition, combination agents (phentermine plus topiramate and naltrexone plus bupropion) are available. These drugs have been intensely studied, and some of their properties are listed in Table 16–5. Clinical trials and phase 4 reports suggest that these agents are modestly effective for the duration of therapy (up to 1 year) and are probably safer than the single-agent amphetamine mimics. However, they do not produce more than a 5–10% loss of weight. Mirabegron, a β3 adrenoceptor agonist approved for the treatment for overactive bladder (see Chapter 9), is of possible future interest because β3 agonists activate brown fat to consume more energy. Sibutramine and rimonabant were marketed for several years but were withdrawn because of increasing evidence of cardiovascular and other toxicities.
Because of the low efficacy and the toxicity of the available drugs, intensive research continues. Because of the redundancy of the physiologic mechanisms for control of body weight, it seems likely that polypharmacy targeting multiple pathways will be needed to achieve success.
TABLE 16–5Antiobesity drugs and their effects. ||Download (.pdf) TABLE 16–5 Antiobesity drugs and their effects.
|Drug or Drug Combination ||Drug Group ||Possible Mechanism of Action ||Dosage ||Toxicity |
GI lipase inhibitor
Reduces lipid absorption
60–120 mg TID PO
Decreased absorption of fat-soluble vitamins, flatulence, fecal incontinence
3 mg/d SC
Nausea, vomiting, pancreatitis
10 mg PO BID
Headache, nausea, dry mouth, dizziness, constipation
Opioid antagonist + antidepressant
32 mg/360 mg PO TID
Headache, nausea, dizziness, constipation
Norepinephrine release in CNS
30–37.5 mg/d PO
Increased BP, HR; arrhythmias, insomnia, anxiety
Sympathomimetic + antiseizure agent
Norepinephrine release plus unknown mechanism
3.75–15 mg/23–92 mg PO
Insomnia, dizziness, nausea, paresthesia, dysgeusia
5-HT1D/1B Agonists & Migraine Headache
The 5-HT1D/1B agonists (triptans, eg, sumatriptan) are used almost exclusively for migraine headache. Migraine in its “classic” form is characterized by an aura of variable duration that may involve nausea, vomiting, visual scotomas or even hemianopsia, and speech abnormalities; the aura is followed by a severe throbbing unilateral headache that lasts for a few hours to 1–2 days. “Common” migraine lacks the aura phase, but the headache is similar. After more than a century of intense study, the pathophysiology of migraine is still poorly understood. Although the symptom pattern and duration of prodrome and headache vary markedly among patients, the severity of migraine headache justifies vigorous therapy in the great majority of cases.
Migraine involves the trigeminal nerve distribution to intracranial (and possibly extracranial) arteries. These nerves release peptide neurotransmitters, especially calcitonin gene-related peptide (CGRP; see Chapter 17), an extremely powerful vasodilator. Substance P and neurokinin A may also be involved. Extravasation of plasma and plasma proteins into the perivascular space appears to be a common feature of animal migraine models and is found in biopsy specimens from migraine patients. This effect probably reflects the action of the neuropeptides on the vessels. The mechanical stretching caused by this perivascular edema may be the immediate cause of activation of pain nerve endings in the dura. The onset of headache is sometimes associated with a marked increase in amplitude of temporal artery pulsations, and relief of pain by administration of effective therapy is sometimes accompanied by diminution of these pulsations.
The mechanisms of action of drugs used in migraine are poorly understood, in part because they include such a wide variety of drug groups and actions. In addition to the triptans, these include ergot alkaloids, nonsteroidal anti-inflammatory analgesic agents, β-adrenoceptor blockers, calcium channel blockers, tricyclic antidepressants and SSRIs, and several antiseizure agents. Furthermore, some of these drug groups are effective only for prophylaxis and not for the acute attack.
Two primary hypotheses have been proposed to explain the actions of these drugs. First, the triptans, the ergot alkaloids, and antidepressants may activate 5-HT1D/1B receptors on presynaptic trigeminal nerve endings to inhibit the release of vasodilating peptides, and antiseizure agents may suppress excessive firing of these nerve endings. Second, the vasoconstrictor actions of direct 5-HT agonists (the triptans and ergot) may prevent vasodilation and stretching of the pain endings. It is possible that both mechanisms contribute in the case of some drugs.
Sumatriptan and its congeners are currently first-line therapy for acute severe migraine attacks in most patients (Figure 16–3). However, they should not be used in patients at risk for coronary artery disease. Anti-inflammatory analgesics such as aspirin and ibuprofen are often helpful in controlling the pain of migraine. Rarely, parenteral opioids may be needed in refractory cases. For patients with very severe nausea and vomiting, parenteral metoclopramide may be helpful.
Effects of sumatriptan (734 patients) or placebo (370 patients) on symptoms of acute migraine headache 60 minutes after injection of 6 mg subcutaneously. All differences between placebo and sumatriptan were statistically significant. (Data from Cady RK et al: Treatment of acute migraine with subcutaneous sumatriptan. JAMA 1991;265:2831.)
Sumatriptan and the other triptans are selective agonists for 5-HT1D and 5-HT1B receptors; the similarity of the triptan structure to that of the 5-HT nucleus can be seen in the structure below. These receptor types are found in cerebral and meningeal vessels and mediate vasoconstriction. They are also found on neurons and probably function as presynaptic inhibitory receptors.
In population studies, all of the triptan 5-HT1 agonists are as effective or more effective in migraine than other acute drug treatments, eg, parenteral, oral, and rectal ergot alkaloids. However, individual drugs in this class may have different efficacies in individual patients. The pharmacokinetics and potencies of the triptans differ significantly and are set forth in Table 16–6. Most adverse effects are mild and include altered sensations (tingling, warmth, etc), dizziness, muscle weakness, neck pain, and for parenteral sumatriptan, injection site reactions. Chest discomfort occurs in 1–5% of patients, and chest pain has been reported, probably because of the ability of these drugs to cause coronary vasospasm. They are therefore contraindicated in patients with coronary artery disease and in patients with angina. Another disadvantage is the fact that their duration of effect (especially that of almotriptan, sumatriptan, rizatriptan, and zolmitriptan, Table 16–6) is often shorter than the duration of the headache. As a result, several doses may be required during a prolonged migraine attack, but their adverse effects limit the maximum safe daily dosage. Naratriptan and eletriptan are contraindicated in patients with severe hepatic or renal impairment or peripheral vascular syndromes; frovatriptan in patients with peripheral vascular disease; and zolmitriptan in patients with Wolff-Parkinson-White syndrome. The brand name triptans are extremely expensive; thus generic sumatriptan should be used whenever possible.
TABLE 16–6Pharmacokinetics of triptans. ||Download (.pdf) TABLE 16–6 Pharmacokinetics of triptans.
|Drug ||Routes ||Time to Onset (h) ||Single Dose (mg) ||Maximum Dose per Day (mg) ||Half-Life (h) |
|Almotriptan ||Oral ||2.6 ||6.25–12.5 ||25 ||3.3 |
|Eletriptan ||Oral ||2 ||20–40 ||80 ||4 |
|Frovatriptan ||Oral ||3 ||2.5 ||7.5 ||27 |
|Naratriptan ||Oral ||2 ||1–2.5 ||5 ||5.5 |
|Rizatriptan ||Oral ||1–2.5 ||5–10 ||30 ||2 |
|Sumatriptan ||Oral, nasal, subcutaneous, rectal ||1.5 (0.2 for subcutaneous) ||25–100 (PO), 20 nasal, 6 subcutaneous, 25 rectal ||200 ||2 |
|Zolmitriptan ||Oral, nasal ||1.5–3 ||2.5–5 ||10 ||2.8 |
Propranolol, amitriptyline, and some calcium channel blockers have been found to be effective for the prophylaxis of migraine in some patients. They are of no value in the treatment of acute migraine. The anticonvulsants valproic acid and topiramate (see Chapter 24) have also been found to have some prophylactic efficacy in migraine. Flunarizine, a calcium channel blocker used in Europe, has been reported in clinical trials to effectively reduce the severity of the acute attack and to prevent recurrences. Verapamil appears to have modest efficacy as prophylaxis against migraine.
Other Serotonin Agonists in Clinical Use
Flibanserin, a 5-HT1a agonist and 5-HT2A antagonist, is approved for treatment of hypoactive sexual desire disorder in women. Due to inadequate evidence of efficacy, it was refused approval in 2010 and 2013. The clinical trials that led to its approval in 2015 showed a very small but significant increase in satisfactory sexual desire and activities over several weeks of daily oral administration. Consumption of alcohol is contraindicated due to increased risk of severe hypotension. Other adverse effects include syncope, nausea, fatigue, dizziness, and somnolence.
Cisapride, a 5-HT4 agonist, was used in the treatment of gastroesophageal reflux and motility disorders. Because of toxicity, it is now available only for compassionate use in the USA. Tegaserod, a 5-HT4 partial agonist, is used for irritable bowel syndrome with constipation (see Chapter 62).
Compounds such as fluoxetine and other SSRIs, which modulate serotonergic transmission by blocking reuptake of the transmitter, are among the most widely prescribed drugs for the management of depression and similar disorders. These drugs are discussed in Chapter 30.
The actions of serotonin, like those of histamine, can be antagonized in several ways. Such antagonism is clearly desirable in those rare patients who have carcinoid tumor and may also be valuable in certain other conditions.
Serotonin synthesis can be inhibited by p-chlorophenylalanine and p-chloroamphetamine. However, these agents are too toxic for general use. Storage of serotonin can be inhibited by the use of reserpine, but the sympatholytic effects of this drug (see Chapter 11) and the high levels of circulating serotonin that result from release prevent its use in carcinoid. Therefore, receptor blockade is the major therapeutic approach to conditions of serotonin excess.
A wide variety of drugs with actions at other receptors (eg, α adrenoceptors, H1-histamine receptors) also have serotonin receptor-blocking effects. Phenoxybenzamine (see Chapter 10) has a long-lasting blocking action at 5-HT2 receptors. In addition, the ergot alkaloids discussed in the last portion of this chapter are partial agonists at serotonin receptors.
Cyproheptadine resembles the phenothiazine antihistaminic agents in chemical structure and has potent H1-receptor-blocking as well as 5-HT2-blocking actions. The actions of cyproheptadine are predictable from its H1 histamine and 5-HT receptor affinities. It prevents the smooth muscle effects of both amines but has no effect on the gastric secretion stimulated by histamine. It also has significant antimuscarinic effects and causes sedation.
The major clinical applications of cyproheptadine are in the treatment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria. The usual dosage in adults is 12–16 mg/d orally in three or four divided doses. It is of some value in serotonin syndrome, but because it is available only in tablet form, cyproheptadine must be crushed and administered by stomach tube in unconscious patients. The drug also appears to reduce muscle spasms following spinal cord injury, in which constitutive activity of 5-HT2C receptors is associated with increases in Ca2+ currents leading to spasms. Anecdotal evidence suggests some efficacy as an appetite stimulant in cancer patients, but controlled trials have yielded mixed results.
Ketanserin blocks 5-HT2 receptors on smooth muscle and other tissues and has little or no reported antagonist activity at other 5-HT or H1 receptors. However, this drug potently blocks vascular α1 adrenoceptors. The drug blocks 5-HT2 receptors on platelets and antagonizes platelet aggregation promoted by serotonin. The mechanism involved in ketanserin’s hypotensive action probably involves α1 adrenoceptor blockade more than 5-HT2 receptor blockade. Ketanserin is available in Europe for the treatment of hypertension and vasospastic conditions but has not been approved in the USA. Ritanserin, another 5-HT2 antagonist, has little or no α-blocking action. It has been reported to alter bleeding time and to reduce thromboxane formation, presumably by altering platelet function.
Ondansetron is the prototypical 5-HT3 antagonist. This drug and its analogs are very important in the prevention of nausea and vomiting associated with surgery and cancer chemotherapy. They are discussed in Chapter 62.
Considering the diverse effects attributed to serotonin and the heterogeneous nature of 5-HT receptors, other selective 5-HT antagonists may prove to be clinically useful.