Histamine and Serotonin: Drugs and Actions PDF

Drugs with Important Actions on Smooth Muscles - Chapter 39: Histamine and Serotonin Overview: - Histamine, serotonin, and prostaglandins belong to a group called autocoids. - Autocoids are heterogenous substances that are formed by the tissues on which they act and, therefore, functi...

Drugs with Important Actions on Smooth Muscles - Chapter 39: Histamine and Serotonin Overview: - Histamine, serotonin, and prostaglandins belong to a group called autocoids. - Autocoids are heterogenous substances that are formed by the tissues on which they act and, therefore, function as local hormones. - These agents have widely differing structures and pharmacologic activities. - The autocoids are different than circulating hormones in that they are produced by many tissues rather than in specific endocrine glands. - This chapter covers autocoids and autocoid antagonists. Histamine - Chemical messenger primarily generated in mast cells - Mediates a wide range of cellular responses - Allergic and inflammatory responses - Gastric acid secretion - Neurotransmission in parts of the brain - Has no clinical application as a drug - Agents that inhibit the action of histamine have important therapeutic applications - Location, synthesis, and release of histamine - Location: - Histamine is present in practically all tissues, with significant amounts in the lungs, skin, blood vessels, and gastrointestinal (GI) tract. - It is found in high concentrations in mast cells and basophils - Functions as a neurotransmitter in the brain - Occurs as a component of venoms and in secretions from insect stings - Synthesis: - Histamine is formed by the decarboxylation of the amino acid histadine by the enzyme histadine decarboxylase. This enzyme is expressed in cells throughout the body. - In mast cells, histamine is stored in granules - If histamine is not stored, it is rapidly inactivated by the enzyme amine oxidase - Release of histamine: - Most often, histamine is just one of several chemical mediators released in response to stimuli - The stimuli for release of histamine from tissues may include destruction of cells as a result of cold, toxins from organisms, venoms from insects and spiders, and trauma - Allergies and anaphylaxis can also trigger significant release of histamine - Mechanism of action - Histamine released in response to certain stimuli exerts its effects by binding to various types of histamine receptors (H~1~, H~2~, H~3~, and H~4~) - H~1~ and H~2~ receptors are widely expressed and are the targets of clinically useful drugs. - Histamine has a wide range of pharmacologic effects: - H~1~ receptors are important in producing smooth muscle contraction and increasing capillary permeability - Histamine promotes vasodilation of small blood vessels by causing the vascular endothelium to release nitric oxide. - Histamine can enhance the secretion of proinflammatory cytokines - H~1~ receptors mediate many pathological processes, including allergic rhinitis, atopic dermatitis, conjunctivitis, urticaria, bronchoconstriction, asthma, and anaphylaxis - Histamine stimulates the parietal cells to cause an increase in acid secretion via activation of H~2~ receptors - Role in allergy and anaphylaxis - Symptoms resulting from intravenous injection of histamine are similar to those associated with anaphylactic shock and allergic reactions - Symptoms result from the release of certain mediators from their storage sites - These mediators include histamine, serotonin, leukotrienes, and the eosinophil chemotactic factor of anaphylaxis. - Leukotrienes- inflammatory mediators- trigger allergic rxn - Eosinophil chemotactic factor of anaphylaxis- present in mast cells, contribute to allergic rxn - In some cases, these mediators cause a localized allergic reaction- ex. skin, respiratory - In other cases, these mediators may cause a full-blown anaphylactic response - It is thought that the difference between these two situations results from differences in the sites from which mediators are released and in their rates of release H~1~ Antihistamines - The term antihistamine refers primarily to the classic H~1~-receptors blockers - Can be divided into first- and second-generation drugs - First-generation - Older but still widely used because they are effective and inexpensive - Most penetrate the central nervous system (CNS) and cause sedation - Tend to interact with other receptors, producing a variety of unwanted adverse effects - Second-generation - Specific for peripheral H~1~ receptors. - Polar, do not penetrate the blood--brain barrier, and cause less CNS depression than the first-generation drugs - Cetirizine and levocetirizine are partially sedating second-generation agents. +-------------+-------------+-------------+-------------+-------------+ | **Drug** | **Actions** | **Therapeut | **Pharmacok | **Adverse | | | | ic | inetics** | Effects** | | | | uses** | | | +=============+=============+=============+=============+=============+ |  | of all | and | absorbed | ation | | | H~1~-recept | inflammator | after oral | H~1~-recept | | *FYI:* | or | y | administrat | or | | | blockers is | conditions* | ion | blockers | | *Cyprohepta | qualitative | * | | have a low | | dine* | ly | | Maximum | specificity | | | similar. | H~1~-recept | serum | , | | *\[SYE-proe | | or | levels | interacting | | -HEP-ta-dee | Most of | blockers | occur at 1 | not only | | n\]* | these | are useful | to 2 hours | with | | | compounds | in treating | | histamine | | *Azelastine | do not | and | Average | receptors | | * | influence | preventing | plasma | but also | | | the | allergic | half-life | with | | *\[a-ZEL-uh | formation | reactions | is 4 to 6 | muscarinic | | -steen\]* | or release | caused by | hours, | cholinergic | | | of | antigens | except for | receptors, | | *ketotifen* | histamine - 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Histamine H~2~-receptor blockers have little, if any, affinity for H~1~ receptors. Although antagonists of the histamine H~2~ receptor block the actions of histamine at all H~2~ receptors, their chief clinical use is as inhibitors of gastric acid secretion in the treatment of ulcers and heartburn. - Some H~2~ blockers may be given in addition to H~1~ blockers in the treatment of urticaria or other allergic type reactions that involve skin reactions. - Serotonin is a neurotransmitter within the enteric nervous system and the CNS. - It plays a role in vasoconstriction, inhibition of gastric secretion, and stimulation of smooth muscle contraction. - Within the GI tract, it may serve as a local hormone to influence GI motility and secretion. - Within the brain, the serotonergic neurons affect mood, appetite, body temperature regulation, and sleep. - While serotonin has no therapeutic uses, serotonin agonists and antagonists are used in the management of several disorders, such as depression and migraine headache. - Location, synthesis, and release of serotonin - Location - Serotonin is largely present within the enterochromaffin cells of the gastrointestinal tract. - It is also found in storage granules in platelets and the raphe nuclei of the brainstem. - Synthesis - Serotonin (also known as 5-hydroxytryptamine, 5-HT) is synthesized from the amino acid l-tryptophan. - Release of serotonin - Following synthesis, serotonin is stored in vesicles and is released by exocytosis of the vesicle in response to an action potential. - The activity of serotonin is terminated by uptake into the neuron and platelets. - Metabolism occurs mainly via monoamine oxidase. - Mechanism of Action - There are several families of 5-HT receptors - Most of these are G protein-coupled receptors, except for 5-HT~3~, which is a ligand-gated cation channel - Serotonin has a wide range of effects that are mediated by the different types of serotonin receptors - Activity at 5-HT~2c~ receptors in the CNS may cause a reduction in appetite - Stimulation of 5-HT~3~ receptors in the GI tract and vomiting center may trigger emesis - Therapeutic Use - Serotonin has a role in the pathophysiology of clinical depression, and agents such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are effective therapies for this condition (see Chapter 17). Drugs Used to Treat Headache Disorders - The most common types of headaches are migraine, tension-type, and cluster headaches. - Patients with severe migraine headaches report one to five attacks per month of moderate to severe pain, which is usually unilateral. - Headache disorders significantly affect quality of life and result in considerable health care costs. - Prevention - Management of headaches involves avoidance of headache triggers (for example, alcohol, chocolate, and stress) and use of abortive treatments for acute headaches, as well as prophylactic therapy in patients with frequent or severe migraines - Treatment - Serotonin agonists (triptans and ergot alkaloids) are effective as abortive agents in the treatment of migraines. - Types of migraine - There are two main types of migraine headaches. - **migraine without aura** - a severe, unilateral, pulsating headache that typically lasts from 2 to 72 hours - often aggravated by physical activity and are accompanied by nausea, vomiting, photophobia (hypersensitivity to light), and phonophobia (hypersensitivity to sound). - The majority of patients with migraine do not have aura. - **migraine with aura** - the headache is preceded by neurologic symptoms called auras, which can be visual, sensory, and/or cause speech or motor disturbances. - Most commonly, these prodromal symptoms are visual (flashes, zigzag lines, and glare) and occur approximately 20 to 40 minutes before headache pain begins. - In the 15% of migraine patients whose headache is preceded by an aura, the aura itself allows diagnosis. - The headache in migraines with or without auras is similar. - Women are threefold more likely than are men to experience either type of migraine. - Biologic basis of migraine headaches - The first manifestation of migraine with aura is a spreading depression of neuronal activity accompanied by reduced blood flow in the most posterior part of the cerebral hemisphere. - This hypoperfusion gradually spreads forward over the surface of the cortex to other contiguous areas of the brain. - The vascular alteration is accompanied by functional changes. - The hypoperfusion persists throughout the aura and well into the headache phase. - Patients who have migraine without aura do not show hypoperfusion. - However, the pain of both types of migraine may be due to extracranial and intracranial arterial vasodilation, which leads to release of neuroactive molecules, such as substance P, neurokinin A, and calcitonin gene--related peptide. - Prodromal symptoms include increased yawning, euphoria, depression, irritability, food cravings, constipation, and neck stiffness - Aura may present as visual, language, sensory, or motor - During the postdrome, patients often feel drained or exhausted, although some report a feeling of mild elation or euphoria - Symptomatic treatment of acute migraine - Acute treatments can be classified as nonspecific (symptomatic) or migraine specific. - Nonspecific treatment includes analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and antiemetics (for example, prochlorperazine) to control vomiting. - Migraine-specific therapy includes serotonin agonists (triptans, ergot alkaloids, and ditans), as well as CGRP receptor antagonists. - Triptans (5-HT~1B/1D~ receptor agonists) - Ergot alkaloids (5-HT~1D~ receptor agonists) - Ditans - CGRP receptor antagonists +-------------+-------------+-------------+-------------+-------------+ | **Drug** | **Actions** | **Therapeut | **Pharmacok | **Adverse | | | | ic | inetics** | Effects** | | | | uses** | | | +=============+=============+=============+=============+=============+ | **Triptans* | Sumatriptan | The onset | Sumatriptan | Elevation | | * | was the | of | is given | of blood | | | first | sumatriptan | subcutaneou | pressure | | **(5-HT~1B/ | available | is 1-2 | sly, | and other | | 1D~ | triptan and | hours when | intranasall | cardiac | | receptor | is the | taken | y, | events have | | agonists)** | prototype | orally | or orally | been | | | of the | | | reported | | *Sumatripta | class | Headache | Zolmitripta | with | | n* | | commonly | n | triptan | | | These | recurs | is given | use- | | *Zolmitript | agents | within 24 | orally and | triptans | | an* | rapidly and | to 48 hours | by nasal | should not | | | effectively | after a | spray | be | | | abort or | single | | administere | | | markedly | dose, but | All other | d | | | reduce the | in most | triptans | to patients | | | severity of | patients, a | are taken | with risk | | | migraine | second dose | orally | factors for | | | headaches | is | | coronary | | | in about | effective | | artery | | | 70% of | in aborting | | disease | | | patients | the | | without | | | | headache\* | | performing | | | It has been | | | a cardiac | | | proposed | Individual | | evaluation | | | that | response to | | prior to | | | activation | triptans | | administrat | | | of 5-HT~1~ | varies, and | | ion. | | | receptors | a trial of | | | | | by these | more than | | Other | | | agents | one triptan | | adverse | | | leads | may be | | events with | | | either to | necessary | | the use of | | | vasoconstri | before | | triptans | | | ction | treatment | | include | | | or to | is | | pain and | | | inhibition | successful. | | pressure | | | of the | | | sensations | | | release of | | | in the | | | proinflamma | | | chest, | | | tory | | | neck, | | | neuropeptid | | | throat, and | | | es | | | jaw. | | | on the | | | Dizziness | | | trigeminal | | | and malaise | | | nerve | | | have also | | | innervating | | | been seen | | | cranial | | | with the | | | blood | | | use of | | | vessels. | | | triptans. | +-------------+-------------+-------------+-------------+-------------+ | **Ergot | Ergotamine | The use of | Ergotamine | Nausea is a | | alkaloids** | and | dihydroergo | | common | | | dihydroergo | tamine | available | adverse | | **(5-HT~1D~ | tamine | is limited | sublinguall | effect | | receptor | are ergot | to severe | y | | | agonists)** | alkaloids | cases of | and is | The ergot | | | | migraines. | mostly | alkaloids | | *Ergotamine | The | | effective | are | | * | mechanism | | when used | contraindic | | | of action | | in the | ated | | *Dihydroerg | is complex, | | early | in patients | | otamine* | with | | stages of | with angina | | | actions at | | the | and | | | 5-HT~1~ | | migraine | peripheral | | | receptors, | | | vascular | | | alpha | | also | disease | | | receptors, | | available | because | | | and | | in an oral | they are | | | dopamine | | tablet and | significant | | | receptors | | rectal | vasoconstri | | | | | suppository | ctors | | | | | as a | | | | | | combination | Should not | | | | | product | be used | | | | | containing | within 24 | | | | | both | hours of | | | | | ergotamine | triptans | | | | | and | due to the | | | | | caffeine | risk of | | | | | | coronary | | | | | used with | ischemia | | | | | strict | | | | | | daily and | Also avoid | | | | | weekly | with potent | | | | | dosage | CYP3A4 | | | | | limits due | inhibitors | | | | | to its | | | | | | ability to | | | | | | cause | | | | | | dependence | | | | | | and rebound | | | | | | headaches | | | | | | | | | | | | Dihydroergo | | | | | | tamine | | | | | | | | | | | | administere | | | | | | d | | | | | | intravenous | | | | | | ly | | | | | | or | | | | | | intranasall | | | | | | y | | | | | | and has an | | | | | | efficacy | | | | | | similar to | | | | | | sumatriptan | | +-------------+-------------+-------------+-------------+-------------+ | **Ditans** | Lasmiditan | Indicted | | Controlled | | | is a | for acute | | substance- | | *Lasmiditan | selective | treatment | | potential | | * | 5-HT~1F~ | of migraine | | for abuse | | | agonist | in patients | | | | *\[las-MID- | | who have | | May cause | | i-tan\]* | Mechanism | contraindic | | significant | | | of action | ations | | driving | | | is unknown | or | | impairment | | | | intolerance | | | | | Does not | to triptans | | | | | cause | | | | | | vasoconstri | | | | | | ction | | | | +-------------+-------------+-------------+-------------+-------------+ | **CGRP | Calcitonin | Rimegepant | | Most common | | receptor | gene-relate | and | | adverse | | antagonists | d | ubrogepant | | effects are | | ** | peptide | are | | nausea and | | | receptor | indicated | | somnolence, | | *Rimegepant | antagonists | in the | | but | | * | | treatment | | incidence | | | CGRP levels | of acute | | is low | | *\[ri-ME-je | are | migraine in | | | | -pant\]* | elevated in | patients | | Avoid using | | | acute | with | | ubrogepant | | *Ubrogepant | migraine | contraindic | | with strong | | * | | ations | | CYP3A4 | | | | or | | inhibitors | | *\[ue-BROE- | | intolerance | | | | je-pant\]* | | to | | | | | | triptans- | | | | | | oral doses | | | +-------------+-------------+-------------+-------------+-------------+ - Prophylaxis for migraine headache - Therapy to prevent migraine is indicated if the attacks occur two or more times a month and if the headaches are severe or complicated by serious neurologic signs. - β-Blockers are often the drugs of choice for migraine prophylaxis; however, calcium channel blockers, anticonvulsants (topiramate and divalproex), antidepressants, and onabotulinumtoxin A may be used. - In addition, oral CGRP antagonists (rimegepant and atogepant) and injectable monoclonal antibodies that are CGRP antagonists (erenumab, galcanezumab, fremanezumab, and eptinezumab) have also shown effectiveness. - Drugs for tension and cluster headache - Analgesics (NSAIDS, acetaminophen, aspirin) are used for symptom relief of tension headaches, with NSAIDs as preferred therapy. - Triptans, along with inhalation of 100% oxygen, are used as first-line abortive strategies for cluster headache. *Per UTD 11/9/24- **First-line agents** -- For most patients with episodic migraine (≤14 hеаdасhе days per month) who have an indication for preventive therapy, we suggest initial treatment with [amitriptyline](https://www.uptodate.com/contents/amitriptyline-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link), [venlafaxine](https://www.uptodate.com/contents/venlafaxine-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link), one of the beta blockers ([metoprolol](https://www.uptodate.com/contents/metoprolol-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link) or [propranolol](https://www.uptodate.com/contents/propranolol-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link)), [topiramate](https://www.uptodate.com/contents/topiramate-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link), or one of the calcitonin gene-related peptide (CGRP) antagonists.* *See UTD chart: Medications for preventive treatment of migraine in adults: Comorbid factors for drug selection* *The presence of associated conditions and comorbid disorders can also help to guide the choice of migrаiոе therapy:* - *For patients with hypertension who are nonsmokers and ≤60 years of age, reasonable options include [metoprolol](https://www.uptodate.com/contents/metoprolol-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link), [propranolol](https://www.uptodate.com/contents/propranolol-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link), or [timolol](https://www.uptodate.com/contents/timolol-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link) in the absence of contraindications to beta blockers.* - *For patients with hypertension who are smokers or are \>60 years of age, options include [verapamil](https://www.uptodate.com/contents/verapamil-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link) or [flunarizine](https://www.uptodate.com/contents/flunarizine-united-states-not-available-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link). We suggest not using beta blockers as initial therapy for migrаine prevention in these patients because beta blockers may be associated with a higher rate of cardiovascular events compared with other antihypertensive drugs in the primary treatment of hypertension. (See [\"Choice of drug therapy in primary (essential) hypertension\"](https://www.uptodate.com/contents/choice-of-drug-therapy-in-primary-essential-hypertension?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link).)* - *For patients with ԁерrеѕsiοn or mood disorder, reasonable options include [amitriptyline](https://www.uptodate.com/contents/amitriptyline-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link) or [venlafaxine](https://www.uptodate.com/contents/venlafaxine-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link).* - *For patients with epilepsy, reasonable options include [valproate](https://www.uptodate.com/contents/valproate-valproic-acid-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link) or [topiramate](https://www.uptodate.com/contents/topiramate-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link).* - *For patients with insomnia, [amitriptyline](https://www.uptodate.com/contents/amitriptyline-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link) is a reasonable option.* - *For patients with obesity, [topiramate](https://www.uptodate.com/contents/topiramate-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link) is a reasonable option.* - *For patients with Raynaud phenomenon, reasonable options include [verapamil](https://www.uptodate.com/contents/verapamil-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link) or [flunarizine](https://www.uptodate.com/contents/flunarizine-united-states-not-available-drug-information?search=migraine%20prophylaxis%20adult&topicRef=3345&source=see_link).* - *For females of childbearing potential, we discuss potential risks of pharmacotherapy. *  A diagram of a patient\'s life cycle Description automatically generated