Histamine, serotonin(1).pdf

# Histamine pharmacology and H1 and H2 blockers This topic explores the fundamental aspects of histamine, including its synthesis, distribution, release mechanisms, and receptor interactions, alongside the pharmacology of its receptor antagonists, H1 and H2 blockers. ### 1.1 Histamine: synthesis, location, release, and effects #### 1.1.1 Synthesis and location Histamine is synthesized from histidine via the enzyme histidine decarboxylase. It is stored in mast cells and basophils within granules, and also found in enterochromaffin-like cells in the stomach, which regulate parietal cell function. Additionally, histaminergic neurons in the tuberomammillary body of the CNS utilize histamine [2](#page=2). #### 1.1.2 Histamine release Histamine release from mast cells can occur through several mechanisms: * **Immunologic degranulation:** In inflammation, complement components C3a and C5a interact with cell surface receptors. In allergic reactions, allergens bind to surface-linked IgE, triggering degranulation [2](#page=2). * **Passive leakage:** Basic drugs such as atropine, amphetamine, morphine, and codeine can displace histamine [2](#page=2). * **Mechanical or chemical damage:** Physical disruption of mast cells, for instance, by snake venom, can lead to release [2](#page=2). #### 1.1.3 Histamine receptors There are four known histamine receptors: * **H1 receptors** are coupled to Gq proteins. They are located on endothelial cells (causing contraction, leading to plasma transudation and edema, and NO release causing vasodilation), smooth muscle cells in the GIT, bronchi, and uterus (causing contraction, significant in asthma), sensory nerve endings (mediating pain and itching), and in the CNS (causing excitation). They also cause vestibular irritation and nausea via the inner ear [3](#page=3). * **H2 receptors** are coupled to Gs proteins. They are found on gastric parietal cells, stimulating HCl secretion. They also affect the heart, causing tachycardia, and the CNS, inducing sedation [3](#page=3). * **H3 receptors** are Gi-coupled presynaptic receptors in the CNS [3](#page=3). * **H4 receptors** are Gi-coupled receptors involved in leukocyte chemotaxis [3](#page=3). #### 1.1.4 Other effects of histamine An intradermal injection of histamine elicits a "triple response": a red center due to vasodilation, a white ring of edema, and a red flare mediated by an axon reflex. In the CNS, histamine plays a role in regulating vital functions such as the sleep-wake cycle, circadian rhythms, appetite, vomiting, learning and memory, and body temperature [4](#page=4). ### 1.2 H1 blockers (antihistamines) #### 1.2.1 Classification and pharmacokinetics H1 blockers are divided into two generations. First-generation antihistamines include clemastine, chlorpyramine, dimetindene, cyproheptadine, promethazine, and azelastine. First-generation agents with antiemetic effects include dimenhydrinate. Second-generation antihistamines include loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine, and bilastine [5](#page=5). **Pharmacokinetics:** * **Administration:** Primarily oral for second-generation drugs and local for first-generation drugs [6](#page=6). * **Blood-Brain Barrier (BBB) Crossing:** Only first-generation drugs readily cross the BBB. Second-generation drugs are substrates for P-glycoprotein (P-gp) and are largely excluded from the CNS [6](#page=6). * **Metabolism:** Undergo CYP metabolism; some, like loratadine, have active metabolites (e.g., desloratadine). Levocetirizine is the active enantiomer of cetirizine [6](#page=6). * **Excretion:** Inactive metabolites are renally excreted [6](#page=6). * **Half-life:** First-generation drugs have a half-life of 4-6 hours, while second-generation drugs have a longer half-life of 12-24 hours [6](#page=6). > **Tip:** The ability of first-generation H1 blockers to cross the BBB explains their prominent sedative effects, whereas second-generation agents are generally non-sedating. #### 1.2.2 Pharmacodynamics H1 blockers exert their effects primarily by blocking H1 receptors. This leads to [7](#page=7): * Inhibition of itching and pain [7](#page=7). * Decreased edema formation [7](#page=7). * Partial prevention of vasodilation (as it is mediated by both H1 and H2 receptors) [7](#page=7). * Sedation (prominent with first-generation drugs) [7](#page=7). * Paradoxical excitation in children [7](#page=7). * Antiemetic effects, acting on receptors in the vestibular apparatus and the vomiting center [7](#page=7). Additional pharmacodynamic properties include: * **5-HT2 blockade:** Seen with cyproheptadine, leading to appetite stimulation [7](#page=7). * **Cholinolytic (atropine-like) effects:** Present in first-generation agents, causing dry mouth, constipation, urinary retention, and blurred vision [7](#page=7). * **Na+ channel blockade:** Observed with promethazine and diphenhydramine, conferring local anesthetic properties [7](#page=7). * **α1 blockade:** Promethazine exhibits this action, contributing to vasodilation [7](#page=7). * **Neuroprotective effect:** Clemastine has shown potential, though clinical trials are controversial [7](#page=7). #### 1.2.3 Indications H1 blockers are indicated for: * **Allergic conditions:** Rhinitis (e.g., seasonal allergies), conjunctivitis, urticaria, atopic dermatitis, insect bites, and drug or food allergies [8](#page=8). * **Nausea and vomiting:** Particularly motion sickness and nausea during pregnancy, often with dimenhydrinate [8](#page=8). * **Insomnia:** Some agents, like dimenhydrinate, can be used for short-term management [8](#page=8). * **Appetite stimulation:** Cyproheptadine is used for this purpose [8](#page=8). * **Premedication in anesthesia** [8](#page=8). * **Local anesthesia** [8](#page=8). **Important Note:** H1 blockers are NOT effective in asthma [8](#page=8). #### 1.2.4 Adverse drug reactions (ADRs) and drug interactions **Common ADRs:** * **Sedation:** A significant ADR of first-generation blockers, leading to reduced concentration, slowed reactions, and impaired ability to drive or operate machinery [9](#page=9). * **Paradoxical excitation:** Can occur in children, potentially leading to seizures [9](#page=9). * **Cholinolytic effects:** Dry mouth, constipation, urinary retention, blurred vision (associated with first-generation agents) [9](#page=9). * **Orthostatic hypotension and tachycardia:** Notably with promethazine [9](#page=9). * **Weight gain:** Associated with cyproheptadine [9](#page=9). * **Allergic reactions:** Possible with topical formulations [9](#page=9). **Drug interactions:** H1 blockers can potentiate the sedative effects of other CNS depressants, including opioid analgesics, sedative-hypnotics, and alcohol [9](#page=9). ### 1.3 H2 blockers #### 1.3.1 Drugs and pharmacokinetics H2 blockers include famotidine, nizatidine, and cimetidine. Ranitidine has been withdrawn from the market due to concerns about a potential carcinogenic excipient [10](#page=10). **Pharmacokinetics:** * **Administration:** Oral and injection [10](#page=10). * **Bioavailability:** Most (except nizatidine) undergo first-pass metabolism, resulting in relatively low oral bioavailability [10](#page=10). * **Metabolism:** Partial hepatic metabolism occurs [10](#page=10). * **Excretion:** Partially renally excreted, undergoing both glomerular filtration and tubular secretion [10](#page=10). * **Half-life:** They generally have short plasma half-lives [10](#page=10). #### 1.3.2 Pharmacodynamics and indications H2 blockers work by blocking H2 receptors on gastric parietal cells. This action primarily inhibits basal and nocturnal gastric acid secretion. Postprandial secretion is less affected as gastrin and acetylcholine are more potent stimulators in this phase. Famotidine is considered a more potent H2 blocker [11](#page=11). **Indications:** * **Gastrointestinal disorders:** Ulcer disease, gastroesophageal reflux disease (GERD), gastritis, and non-ulcer dyspepsia when taken orally [11](#page=11). * **Bleeding prevention:** Used intravenously to prevent stress ulcer bleeding [11](#page=11). #### 1.3.3 Adverse drug reactions (ADRs) and drug interactions **ADRs with oral administration:** These are uncommon, and H2 blockers are generally considered safe. Reported effects include diarrhea, constipation, headache, and fatigue [12](#page=12). **ADRs with intravenous administration:** These can be more significant due to blockade of cardiac and CNS H2 receptors, potentially causing bradycardia, hypotension, confusion, and hallucinations [12](#page=12). **Specific ADRs of Cimetidine:** Cimetidine is associated with more pronounced ADRs, including mental status changes (especially in the elderly), hyperprolactinemia leading to galactorrhea-dysmenorrhea in women and infertility, and antiandrogenic effects such as gynecomastia and impotence [12](#page=12). **Drug interactions:** Cimetidine is a potent inhibitor of CYP enzymes, leading to significant drug interactions by affecting the metabolism of other medications [12](#page=12). --- # Serotonin and its receptor interactions Serotonin, also known as 5-hydroxytryptamine (5-HT), functions as both a neurotransmitter and a local hormone, playing a critical role in various physiological processes across the body [13](#page=13). ### 1.1 Serotonin synthesis, degradation, and distribution The synthesis of serotonin begins with the amino acid tryptophan, which is converted to 5-hydroxytryptophan, and subsequently to 5-hydroxytryptamine. In the pineal gland, serotonin is further transformed into melatonin. The primary enzyme responsible for serotonin degradation is monoamine oxidase (MAO), which breaks it down into 5-hydroxyindoleacetic acid (5-HIAA) [13](#page=13). Serotonin is distributed throughout the body in several key locations: * **Gastrointestinal Tract (GIT):** Approximately 90% of serotonin is found in the GIT, produced by enterochromaffin cells and serotonergic neurons within the enteric nervous system (ENS) [13](#page=13). * **Platelets:** Serotonin is stored in platelets and plays a role in platelet aggregation [13](#page=13). * **Central Nervous System (CNS):** Serotonergic neuron cell bodies are primarily located in the raphe nuclei. In the CNS, serotonin is involved in the regulation of mood, sleep, appetite, body temperature, blood pressure, pain perception, and vomiting. Dysregulation of serotonergic systems is implicated in conditions such as depression, anxiety, schizophrenia, eating disorders, and migraine pathogenesis [13](#page=13). ### 1.2 Serotonergic receptor types and functions Serotonin exerts its diverse effects by interacting with a variety of receptor subtypes, each with distinct locations and signaling pathways [14](#page=14). | Receptor Type | G-protein Coupling | Localization | Primary Function(s) | Associated Drug Classes | | :------------ | :----------------- | :----------------------------------------------------------- | :---------------------------------------------------------------------------------- | :------------------------------- | | 5-HT1A | $G_i$ | CNS (presynaptic) | Presynaptic inhibitory | Buspirone (+) | | 5-HT1B | $G_i$ | Cerebral blood vessels, CNS (incl. trigeminal ganglia) | Vasoconstriction, presynaptic inhibitory | Triptans (+) | | 1D | $G_i$ | Blood vessels, CNS (incl. trigeminal ganglia) | Vasoconstriction, presynaptic inhibitory | Triptans (+) | | 5-HT1E | $G_i$ | CNS | Not explicitly defined in the provided text | N/A | | 5-HT1F | $G_i$ | Trigeminal ganglia, etc. | Presynaptic inhibitory | Lasmiditan (+) | | 5-HT1P | $G_0$ | Enteric NS | Not explicitly defined in the provided text | N/A | | 5-HT2A | $G_q$ | Platelets, smooth muscle, cortex, immune cells | Platelet aggregation, smooth muscle contraction | Cyproheptadine (+) | | 5-HT2B | $G_q$ | Stomach fundus | Smooth muscle contraction | N/A | | 5-HT2C | $G_q$ | Choroid plexus, CNS | Cerebrospinal fluid production | Lorcaserin (+) | | 5-HT3 | Ligand-gated ion channel | Peripheral NS, CTZ, GIT | Pain, vomiting | Setrons (-) | | 5-HT4 | $G_s$ | CNS, GIT | Prokinetic effect (via acetylcholine release in ENS) | Metoclopramide (+) | | 5-HT5A, B | $G_i$ | CNS | Not explicitly defined in the provided text | N/A | | 5-HT6 | $G_s$ | CNS | Not explicitly defined in the provided text | N/A | | 5-HT7 | $G_s$ | CNS, GIT | Not explicitly defined in the provided text | Clozapine (-) | *Note: (+) indicates agonism or activation, (-) indicates antagonism or blockade.* #### 1.2.1 Complex effects of serotonin in different systems Serotonin exerts multifaceted effects across various physiological systems, often mediated by specific receptor subtypes [15](#page=15). * **Cardiovascular System (CVS):** * Serotonin can induce meningeal and cerebral vasoconstriction via 5-HT1B/D receptors [15](#page=15). * It causes vasoconstriction of larger vessels through 5-HT2A receptors [15](#page=15). * Nitric oxide (NO)-mediated arteriolar vasodilation is also a function of serotonin, particularly through 5-HT1 receptors [15](#page=15). * Serotonin promotes platelet aggregation via 5-HT2A receptors [15](#page=15). * **Gastrointestinal Tract (GIT):** * Serotonin stimulates smooth muscle contraction in the esophagus (5-HT4), stomach fundus (5-HT2B), and intestines (5-HT2A) [15](#page=15). * It contributes to a prokinetic effect by promoting acetylcholine release in the enteric nervous system through 5-HT4 receptors [15](#page=15). * **Role in Inflammation:** * Serotonin plays a role in inflammation, influencing T-lymphocyte maturation, chemotaxis, and the secretion of inflammatory mediators, predominantly via 5-HT2A receptors [15](#page=15). > **Tip:** Understanding the specific receptor subtype and its associated G-protein coupling ($G_i$, $G_q$, $G_s$, or ligand-gated ion channel) is crucial for predicting the downstream cellular effect of serotonin. Pay close attention to the functional consequences of each receptor's activation or blockade, as indicated by the associated drug classes. --- # Drugs affecting serotonergic neurotransmission This topic details various drugs that modulate serotonergic pathways by acting as agonists, partial agonists/antagonists, antagonists, or reuptake inhibitors at different serotonin (5-HT) receptors. ### 3.1 Serotonin agonists #### 3.1.1 5-HT$_{1A}$ receptor agonists: Buspirone Buspirone is used to treat generalized anxiety, but not acute symptoms [17](#page=17). **Pharmacokinetics:** * Undergoes a significant first-pass effect [17](#page=17). * Has active metabolites with long half-lives; the main metabolite is an $\alpha_2$ receptor antagonist, though its importance is unknown [17](#page=17). * The parent drug has a plasma half-life of 3-4 hours [17](#page=17). **Pharmacodynamics:** * Acts as a full agonist on presynaptic inhibitory 5-HT$_{1A}$ receptors, which decreases serotonin release [17](#page=17). * Acts as a partial agonist on postsynaptic 5-HT$_{1A}$ receptors in the cortex, leading to decreased serotonin action [17](#page=17). * Produces an anxiolytic effect that develops slowly over 2-4 weeks [17](#page=17). **Adverse Drug Reactions (ADRs):** * May cause chest pain, tachycardia, and palpitations [17](#page=17). * Common side effects include dizziness, headache, and paresthesias [17](#page=17). * Gastrointestinal discomfort can occur [17](#page=17). * Importantly, buspirone does not cause sedation, does not impair driving ability, and is not addictive [17](#page=17). * **Drug interactions:** Concurrent use with MAO-inhibitors can lead to an increase in respiratory rate (RR) [17](#page=17). #### 3.1.2 5-HT$_{1B/D}$ receptor agonists: Triptans Triptans are used to treat migraine attacks and should not be used for more than two doses per day or for longer than 2-3 days [18](#page=18). **Pharmacokinetics:** * Available via various administration routes, including nasal, rectal, and subcutaneous [18](#page=18). * Oral administration leads to onset of action in 1-3 hours, with faster onset via other routes [18](#page=18). * Not all triptans effectively cross the blood-brain barrier (BBB) as they are substrates for P-glycoprotein (P-gp) [18](#page=18). * Most have short plasma half-lives (2-6 hours) and short durations of action, with Frovatriptan being an exception [18](#page=18). **Pharmacodynamics:** * Activation of 5-HT$_{1B}$ and 5-HT$_{1D}$ receptors causes: * Intracranial (cerebral and meningeal) vasoconstriction [18](#page=18). * Decreased release of peptides, particularly CGRP (calcitonin gene-related peptide), from trigeminal nerve endings [18](#page=18). **Adverse Drug Reactions (ADRs):** * Common ADRs include paresthesias, fatigue, dizziness, and nausea [18](#page=18). * Some patients experience neck, chest, or jaw discomfort, tightness, or pain [18](#page=18). **Contraindications:** * Patients with coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular syndromes should not use triptans due to their vasoconstrictor effects [18](#page=18). #### 3.1.3 5-HT$_{1F}$ receptor agonists: Lasmiditan Lasmiditan is used for the treatment of migraine attacks [19](#page=19). **Pharmacokinetics:** * Administered orally [19](#page=19). * Crosses the BBB [19](#page=19). * Metabolized by CYP2D6 [19](#page=19). * Has a short plasma half-life of 6 hours [19](#page=19). **Pharmacodynamics:** * Acts as a 5-HT$_{1F}$ receptor agonist, leading to decreased peptide release (especially CGRP) from trigeminal ganglia [19](#page=19). * Modulates ascending and descending pain pathways [19](#page=19). * Critically, it has **no vasoconstrictor effect** [19](#page=19). **Adverse Drug Reactions (ADRs):** * Common side effects include dizziness, vertigo, and fatigue [19](#page=19). * Concerns regarding cardiovascular (CV) safety have been noted [19](#page=19). #### 3.1.4 5-HT$_{4}$ receptor agonists: Metoclopramide Metoclopramide is a prokinetic and antiemetic agent [20](#page=20). **Pharmacokinetics:** * Well absorbed orally and crosses the BBB [20](#page=20). * Metabolism is primarily through phase 2 reactions, with renal excretion [20](#page=20). * Has a short plasma half-life [20](#page=20). **Pharmacodynamics:** * As a 5-HT$_{4}$ receptor agonist, it increases acetylcholine release in the enteric nervous system (ENS) [20](#page=20). * Dopamine D2 receptor blockade also activates cholinergic smooth muscle stimulation [20](#page=20). * **Prokinetic action:** * Activates proximal gastrointestinal (GI) peristalsis in the esophagus and stomach [20](#page=20). * Increases the tone of the lower esophageal sphincter [20](#page=20). * Stimulates stomach emptying [20](#page=20). * **Additional antiemetic action:** Achieved through 5-HT$_{3}$ and D2 receptor blockade in the chemoreceptor trigger zone (CTZ) [20](#page=20). **Indications:** * Gastroesophageal reflux disease (GERD) [21](#page=21). * Gastroparesis, particularly after surgery or in diabetic neuropathy [21](#page=21). * Vomiting [21](#page=21). **Adverse Drug Reactions (ADRs):** * ADRs are primarily due to D2 receptor blockade in different pathways: * **Mesolimbic/mesocortical pathway:** Can cause agitation, sleepiness/insomnia, anxiety, and excitation [21](#page=21). * **Nigro-striatal pathway:** Leads to extrapyramidal effects such as Parkinson-like tremor, akathisia, and acute dystonias [21](#page=21). * **Tubero-infundibular pathway:** Results in hyperprolactinemia with galactorrhea, gynecomastia, impotence in men, and menstrual changes in women [21](#page=21). ### 3.2 5-HT receptor partial agonists/antagonists: Ergotamine Ergotamine is derived from alkaloids produced by the fungus *Claviceps purpurea*. It is a partial agonist at 5-HT$_{1}$, 5-HT$_{2}$, and $\alpha$ adrenergic receptors [22](#page=22) [23](#page=23). **Pharmacokinetics:** * Low oral bioavailability, which is enhanced when taken with caffeine [23](#page=23). * Dihydroergotamine, a semi-synthetic derivative, has higher bioavailability [23](#page=23). **Pharmacodynamics:** * Acts as a partial agonist of 5-HT$_{1}$, 5-HT$_{2}$ (pre- and postsynaptic), and $\alpha$ adrenergic receptors [23](#page=23). * Causes generalized vasoconstriction [23](#page=23). * Decreases CGRP release in the trigeminal ganglia [23](#page=23). **Indication:** * Migraine attack [23](#page=23). **Adverse Drug Reactions (ADRs):** * GI disturbances such as diarrhea, nausea, and vomiting [23](#page=23). * Can cause vasoconstriction leading to gangrene [23](#page=23). **Contraindications:** * Vascular diseases including CAD, cerebrovascular disease, and peripheral vascular syndromes [23](#page=23). * Pregnancy [23](#page=23). **Intoxication Symptoms (Ergotism):** * Can manifest as dementia, florid hallucinations [22](#page=22). * Prolonged and generalized vasospasm that can lead to gangrene [22](#page=22). * Causes uterine contractions, potentially leading to abortion in pregnancy [22](#page=22). ### 3.3 Serotonin antagonists #### 3.3.1 5-HT$_{2A}$ receptor antagonists: Cyproheptadine Cyproheptadine is used for specific indications including carcinoid syndrome and cold-induced urticaria [24](#page=24). **Pharmacokinetics:** * Pharmacokinetics are similar to first-generation H1 blockers [24](#page=24). **Pharmacodynamics:** * Acts as a 5-HT$_{2A}$ receptor antagonist [24](#page=24). * Also blocks H1 and muscarinic cholinergic receptors [24](#page=24). **Indications:** * Carcinoid syndrome, where symptoms are due to excess serotonin release [24](#page=24). * Cold-induced urticaria [24](#page=24). * Appetite stimulation, particularly in children and cancer patients [24](#page=24). **Adverse Drug Reactions (ADRs):** * Sedation [24](#page=24). * Cholinolytic effects [24](#page=24). #### 3.3.2 5-HT$_{3}$ receptor antagonists (Setrons) Setrons are used to manage nausea and vomiting, particularly those associated with cytotoxic therapies and postoperative states [25](#page=25). **Pharmacokinetics:** * Available in oral and intravenous dosage forms; Granisetron also comes as a transdermal therapeutic system (TTS) [25](#page=25). * Metabolized in the liver by CYP enzymes [25](#page=25). * Excreted via renal and biliary routes [25](#page=25). * Most have short plasma half-lives of 4-9 hours [25](#page=25). * Palonosetron is an exception with a long half-life of 40 hours [25](#page=25). **Pharmacodynamics:** * Act as 5-HT$_{3}$ receptor antagonists in the CTZ and ENS [25](#page=25). * They prevent nausea and vomiting caused by the degradation of serotonin-containing cells in the GI tract, which leads to consecutive activation of the ENS and the vomiting center [25](#page=25). **Indications:** * Nausea and vomiting caused by cytotoxic therapies (chemotherapy, radiation therapy) [25](#page=25). * Postoperative nausea and vomiting [25](#page=25). **Adverse Drug Reactions (ADRs):** * Common side effects include headache, dizziness, and constipation [25](#page=25). * QT interval prolongation can occur, notably with Dolasetron [25](#page=25). **Drug Interactions:** * There is a probability of serotonin syndrome when combined with other serotonin-elevating drugs [25](#page=25). ### 3.4 5-HT reuptake inhibitors: Antidepressants (Note: The provided document content only lists "antidepressants" under this category without further pharmacological details. A comprehensive summary would require more information.) --- # Migraine pathogenesis and treatment Migraine is a complex, chronic cerebrovascular disease characterized by recurrent, disabling headache attacks, often accompanied by other symptoms, and involves specific pathophysiological mechanisms and a range of treatment options [26](#page=26). ### 4.1 Understanding migraine Migraine is a chronic cerebrovascular disease affecting a significant portion of the population, predominantly women. It is defined by recurrent disabling headache attacks, which can be unilateral or bilateral. These attacks are frequently accompanied by symptoms such as nausea, vomiting, phonophobia (sensitivity to sound), and photophobia (sensitivity to light). Migraine attacks can vary in duration, lasting from hours to days, and are followed by symptom-free periods. The condition can manifest as episodic migraine, or chronic migraine, which is characterized by at least 15 days of headache per month, with at least 8 of those days being migraine attacks. Migraine can also be associated with the menstrual cycle [26](#page=26). #### 4.1.1 Phases of migraine Migraine attacks typically progress through four distinct phases: * **Prodromal phase:** This phase can occur hours to days before the headache and is associated with activation of thalamic and hypothalamic centers. Symptoms may include irritability, mood swings, hunger, fatigue, and phonophobia [27](#page=27). * **Aura:** The aura is a neurological symptom that may precede the headache by up to 24 hours. It is caused by spreading cortical depression [26](#page=26) [27](#page=27). * **Attack phase:** This is the phase of the headache itself, characterized by disabling pain and associated symptoms [26](#page=26). * **Postdromal phase:** This phase follows the headache attack [26](#page=26). #### 4.1.2 Pathogenesis of migraine The pathogenesis of migraine involves several key mechanisms: * **Triggers:** Provoking factors for migraine can include stress, alcohol, certain foods, hormonal changes, or may be absent [27](#page=27). * **Cortical spreading depression:** The aura phase is believed to be initiated by spreading cortical depression [27](#page=27). * **Trigeminal nerve activation:** Spreading cortical depression leads to the activation of trigeminal ganglia [27](#page=27). * **Mediator release:** Activated trigeminal nerves release algogenic mediators, notably CGRP (calcitonin gene-related peptide), as well as substance P and VIP [27](#page=27). * **Neuropeptide effects:** These neuropeptides cause vasodilation, aseptic inflammation in the vessel wall, and contribute to pain perception [27](#page=27). ### 4.2 Treatment for acute migraine attacks The management of acute migraine attacks involves various pharmacological approaches, tailored to the severity of the attack: #### 4.2.1 Non-specific and symptomatic treatments * **Non-opioid analgesics and NSAIDs:** These are generally considered the first-line drugs of choice for mild to moderate attacks [28](#page=28). * **Metoclopramide:** This drug is used to treat nausea and vomiting, prevent stomach stasis, and improve the absorption of other medications [28](#page=28). #### 4.2.2 Specific migraine-abortive medications * **Triptans:** These are indicated for more severe migraine attacks [28](#page=28). * **Lasmiditan:** This medication is an option when triptan use is contraindicated, such as in patients with vascular disease [28](#page=28). * **Ubrogepant:** * This is a CGRP receptor antagonist [28](#page=28). * CGRP receptors are located on intracranial blood vessels, trigeminal ganglia, and within the central nervous system [28](#page=28). * It is used for migraine attacks when other drugs have been ineffective [28](#page=28). * Potential adverse drug reactions (ADRs) include nausea, vomiting, and xerostomia (dry mouth) [28](#page=28). * **Ergot alkaloids:** These are generally not recommended due to their toxicity [28](#page=28). #### 4.2.3 Combination therapies Combinations of medications are permissible, but the co-administration of two serotonergic drugs should be avoided due to the risk of serotonin syndrome [28](#page=28). ### 4.3 Preventive migraine therapies Preventive treatments are considered when migraine attacks are frequent and prolonged. A careful evaluation of the risk-benefit ratio is essential before initiating these therapies [29](#page=29). #### 4.3.1 Classes of preventive medications and their proposed mechanisms A variety of drug classes are used for migraine prophylaxis, with proposed mechanisms of action including: * **Beta-blockers (e.g., Propranolol):** Believed to exert a membranostabilizing action [29](#page=29). * **Antiepileptics (e.g., Valproic acid, Carbamazepine, Gabapentine, Topiramate):** These medications are thought to prevent hyperexcitability of trigeminal nerves [29](#page=29). * **Tricyclic antidepressants:** These may help by stimulating the endogenous antinociceptive system [29](#page=29). * **Calcium channel blockers (e.g., Verapamil, Flunarizine, Nimodipine):** [29](#page=29). * **Alpha-2 agonists (e.g., Clonidine):** Proposed to work by decreasing neurotransmitter release [29](#page=29). * **Cyproheptadine:** [29](#page=29). * **Erenumab:** This is a newer monoclonal antibody that targets the CGRP receptor. Information regarding its long-term effects is still emerging [29](#page=29). --- ## Common mistakes to avoid - Review all topics thoroughly before exams - Pay attention to formulas and key definitions - Practice with examples provided in each section - Don't memorize without understanding the underlying concepts

| Term | Definition | |------|------------| | Histidine decarboxylase | An enzyme responsible for catalyzing the decarboxylation of histidine to histamine. This is a key step in the biosynthesis of histamine. | | Mastocytes | These are immune cells found in connective tissues throughout the body. They play a crucial role in allergic reactions and inflammation by releasing histamine and other mediators from their granules. | | Basophils | A type of white blood cell that circulates in the blood. They are similar to mast cells in that they contain granules filled with histamine and other inflammatory mediators, and are involved in allergic responses. | | Enterochromaffin-like cells (ECL cells) | Specialized cells found in the stomach lining that produce and secrete histamine, which in turn stimulates parietal cells to produce hydrochloric acid. | | Tuberomammillary body | A nucleus in the posterior hypothalamus that contains histaminergic neurons. These neurons project widely throughout the brain and are involved in regulating sleep-wake cycles and other vital functions. | | Immunologic degranulation | The process by which mast cells release their granular contents, including histamine, in response to immune triggers such as allergens binding to IgE antibodies on the cell surface. | | Complement components (C3a, C5a) | Fragments produced during the activation of the complement system, an important part of the innate immune system. These components can directly trigger mast cell degranulation. | | Basic drugs | Certain drugs with a basic chemical structure that can displace histamine from mast cell granules, leading to its release. Examples include amphetamine and morphine. | | Histamine receptors (H1, H2, H3, H4) | Transmembrane proteins that bind histamine, initiating intracellular signaling pathways. H1 receptors are primarily involved in allergic reactions, inflammation, and CNS excitation; H2 receptors regulate gastric acid secretion and heart rate; H3 and H4 receptors are found in the CNS and immune cells, respectively, with inhibitory roles. | | Gq protein-coupled receptor | A type of receptor that, upon activation, signals through the Gq protein pathway, leading to the activation of phospholipase C and downstream effects like calcium mobilization. H1 receptors are Gq-coupled. | | Gs protein-coupled receptor | A type of receptor that, upon activation, signals through the Gs protein pathway, typically leading to the stimulation of adenylyl cyclase and increased cyclic AMP levels. H2 receptors are Gs-coupled. | | Gi protein-coupled receptor | A type of receptor that, upon activation, signals through the Gi protein pathway, which generally inhibits adenylyl cyclase, leading to decreased cyclic AMP levels. H3 and H4 receptors are Gi-coupled. | | Endothelium | The inner lining of blood vessels. Histamine acting on endothelial cells causes contraction, leading to increased vascular permeability and edema, and can also stimulate nitric oxide (NO) release, causing vasodilation. | | NO release | Nitric oxide is a signaling molecule that causes vasodilation by relaxing smooth muscle cells in blood vessel walls. | | Plasma transudation | The leakage of fluid from blood vessels into surrounding tissues, contributing to edema. This occurs due to increased vascular permeability induced by histamine. | | Axon reflex | A reflex arc that occurs within a single sensory neuron, where a stimulus at one point on the axon triggers a response that travels in both directions, including antidromic conduction to sensory nerve endings, causing vasodilation and a flare response. | | Histaminergic CNS neurons | Neurons in the brain that use histamine as their primary neurotransmitter. These neurons, originating in the tuberomammillary body, are involved in regulating wakefulness, appetite, and cognitive functions. | | Triple response | A characteristic local reaction to intradermal injection of histamine, consisting of a red spot at the injection site (vasodilation), a surrounding red flare (axon reflex), and a pale wheal (edema). | | Blood-brain barrier (BBB) | A protective barrier formed by specialized endothelial cells in the brain's capillaries that restricts the passage of substances from the bloodstream into the brain tissue. Some drugs can cross this barrier, while others cannot. | | P-gp substrates | P-glycoprotein (P-gp) is an efflux transporter that can pump drugs out of cells, including across the blood-brain barrier. Drugs that are P-gp substrates are often poorly distributed into the central nervous system. | | CYP metabolism | Cytochrome P450 (CYP) enzymes are a group of liver enzymes primarily responsible for metabolizing a wide range of drugs and endogenous compounds. | | Enantiomer | One of a pair of molecules that are mirror images of each other but cannot be superimposed. Levocetirizine is the (S)-enantiomer of cetirizine. | | Xerostomia | Dry mouth, a common side effect of medications with anticholinergic properties. | | Orthostatic hypotension | A drop in blood pressure that occurs when standing up from a sitting or lying position. | | Serotonin (5-hydroxytryptamine, 5-HT) | A neurotransmitter and local hormone synthesized from tryptophan. It plays critical roles in regulating mood, sleep, appetite, gut motility, and platelet aggregation. | | Tryptophan | An essential amino acid that serves as the precursor for the synthesis of serotonin. | | 5-hydroxytryptophan (5-HTP) | An intermediate in the synthesis of serotonin from tryptophan. | | Monoamine oxidase (MAO) | An enzyme that metabolizes monoamine neurotransmitters, including serotonin. Inhibition of MAO increases serotonin levels. | | 5-HIAA | 5-hydroxyindoleacetic acid, the main metabolite of serotonin, used as a biomarker for serotonin turnover. | | Enteric Nervous System (ENS) | The intrinsic nervous system of the gastrointestinal tract, often referred to as the 'second brain', which controls gut motility and secretion. | | Nuclei raphe | A group of nuclei in the brainstem that contain the cell bodies of serotonergic neurons. | | Ligand-gated ion channel | A transmembrane receptor that opens or closes a channel in response to binding of a specific ligand (e.g., a neurotransmitter). The 5-HT3 receptor is an example. | | Prokinetic effect | An effect that increases gastrointestinal motility and promotes the movement of contents through the digestive tract. | | CTZ (Chemoreceptor Trigger Zone) | An area in the brainstem that detects emetic signals in the blood and relays them to the vomiting center, inducing nausea and vomiting. | | Carcinoid syndrome | A condition caused by a rare tumor (carcinoid) that secretes excessive amounts of serotonin and other substances, leading to symptoms like flushing, diarrhea, and bronchospasm. | | Motor neuron | A nerve cell that controls muscle movement. | | Extraspyramidal effects | A group of movement disorders, such as tremor, rigidity, and akathisia, caused by disruption of dopamine pathways in the brain, often as a side effect of antipsychotic medications or metoclopramide. | | Nigro-striatal pathway | A dopamine pathway in the brain that connects the substantia nigra to the striatum. It is crucial for motor control. | | Tubero-infundibular pathway | A dopamine pathway in the hypothalamus that regulates prolactin secretion. | | Hyperprolactinemia | Elevated levels of the hormone prolactin in the blood, which can be caused by drugs that block dopamine receptors. | | Galactorrhea | Inappropriate production and discharge of milk from the breasts, often a symptom of hyperprolactinemia. | | Gynecomastia | Abnormal enlargement of breast tissue in males. | | Claviceps purpurea | A fungus that infects cereal crops, producing ergot alkaloids which have significant pharmacological effects. | | Ergot alkaloids | A group of psychoactive compounds produced by the ergot fungus. They have complex pharmacological actions on adrenergic, dopaminergic, and serotonergic receptors. | | LSD (Lysergic acid diethylamide) | A potent hallucinogenic drug derived from ergot alkaloids. | | Ergometrine | An ergot alkaloid that causes uterine contractions. | | Ergotamine | An ergot alkaloid used in the treatment of migraine, acting as a vasoconstrictor. | | Bromocriptine | A dopamine agonist derived from ergot alkaloids, used to treat conditions like Parkinson's disease and hyperprolactinemia. | | Ergotism | A condition caused by consuming ergot-contaminated grain, characterized by symptoms such as hallucinations, gangrene, and neurological disturbances. | | Setrons | A class of drugs that antagonize 5-HT3 receptors, primarily used to prevent nausea and vomiting. Examples include ondansetron, granisetron, and tropisetron. | | TTS (Transdermal Therapeutic System) | A drug delivery system that allows medication to be absorbed through the skin into the bloodstream over a prolonged period. | | QT interval prolongation | An electrocardiographic finding indicating a delay in ventricular repolarization, which can increase the risk of potentially fatal cardiac arrhythmias. | | Serotonin syndrome | A potentially life-threatening condition caused by excessive serotonergic activity in the central nervous system, often due to interactions between multiple serotonergic drugs. | | Migraine | A common neurological disorder characterized by recurrent, disabling headache attacks, often accompanied by nausea, vomiting, and sensitivity to light and sound. | | Prodromal phase | The initial phase of a migraine attack, which can occur hours or days before the headache and is characterized by subtle neurological or psychological symptoms. | | Aura | A transient neurological symptom that typically precedes or accompanies a migraine headache. It often involves visual disturbances, sensory changes, or speech difficulties. | | Spreading cortical depression | A wave of neuronal and glial depolarization that spreads slowly across the surface of the cerebral cortex. It is believed to be the underlying mechanism of migraine aura. | | Trigeminal ganglia | A cluster of nerve cell bodies located in the face that contains sensory neurons of the trigeminal nerve, which innervates the face and head. Activation of these ganglia plays a key role in migraine pain. | | Algogenic mediators | Substances that cause pain. In migraine, neuropeptides like CGRP and substance P released from trigeminal nerves are considered algogenic mediators. | | CGRP (Calcitonin Gene-Related Peptide) | A neuropeptide involved in pain transmission and vasodilation, particularly implicated in the pathogenesis of migraine. | | Substance P | A neuropeptide that acts as a neurotransmitter and plays a role in pain sensation and inflammation. | | VIP (Vasoactive Intestinal Peptide) | A neuropeptide involved in regulating smooth muscle contraction and relaxation, and also implicated in pain and inflammation. | | NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) | A class of drugs that reduce pain, inflammation, and fever. Examples include ibuprofen and naproxen. | | Stomach stasis | A condition where the stomach empties its contents more slowly than normal. | | Ubrogepant | A CGRP receptor antagonist used for the acute treatment of migraine. | | Beta-blockers | A class of drugs that block the effects of adrenaline on the heart and blood vessels, used in various cardiovascular conditions and also for migraine prophylaxis. Propranolol is an example. | | Membranostabilizing action | An effect that stabilizes the cell membrane, which can influence neuronal excitability and neurotransmitter release. | | Antiepileptic drugs | Medications used to prevent or treat seizures. Some, like valproic acid and topiramate, are also effective in migraine prophylaxis. | | Tricyclic antidepressants (TCAs) | A class of antidepressants that can also be used for migraine prevention, possibly by modulating pain pathways. | | Endogenous antinociceptive system | The body's own system for inhibiting pain perception. | | Ca channel blockers | Drugs that block calcium channels, affecting smooth muscle contraction and neuronal excitability. Used in cardiovascular conditions and migraine prophylaxis. | | Alpha-2 agonists | Drugs that stimulate alpha-2 adrenergic receptors, leading to decreased neurotransmitter release. Clonidine is an example used for blood pressure control and migraine prophylaxis. | | Erenumab | A monoclonal antibody that targets the CGRP receptor, used for migraine prevention. |