Histamine
Histamine is a chemical messenger that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in parts of the brain. Histamine has no clinical applications.
A. Location, synthesis, and release
1.Location: Histamine occurs in practically all tissues, , with high amounts found in lung, skin, and the gastrointestinal tract . It is found at high concentration in mast cells or basophiles.
2.Synthesis: Histamine is an amine formed by the decarboxylation of the amino acid histidine by histidine decarboxylase . In mast cells, histamine is stored in granules as an inactive complex composed of histamine and the, heparin. If histamine is not stored, it is rapidly inactivated by amine oxidase enzymes.
3- Release of histamine: The release of histamine may be the primary response to some stimuli. Stimuli causing the release of histamine from tissues include the destruction of cells as a result of cold, bacterial toxins, bee sting venoms, or trauma. Allergies and anaphylaxis can also trigger release of histamine.
B. Mechanism of action :Histamine released in response to various stimuli exerts its effects by binding to one or more of four types of histamine receptors - H1, H2, H3, and H4 receptors. H1 and H2 receptors are widely expressed and are the targets of clinically useful drugs. H3 and H4 receptors are expressed in only a few cell types, and their roles in drug action are unclear. All types of histamine receptors have seven transmembrane helical domains and transduce extracellular signals by way of G protein mediated second-messenger systems. Some of histamine's wide range of pharmacologic effects are mediated by both H1 and H2 receptors, whereas others are mediated by only one class. For example, the H1 receptors are important in producing smooth muscle contraction and increasing capillary permeability. Histamine promotes vasodilation by causing vascular endothelium to release nitric oxide. This chemical signal diffuses to the vascular smooth muscle, where it stimulates cyclic guanosine monophosphate production, causing vasodilation. Histamine H2 receptors mediate gastric acid secretion. In contrast, stimulation of H2 receptors enhances the production of cyclic adenosine monophosphate (cAMP) by adenylyl cyclase.
C. Role in allergy and anaphylaxis
The symptoms resulting from intravenous injection of histamine are similar to those associated with anaphylactic shock and allergic reactions. These include contraction of smooth muscle, stimulation of secretions, dilation and increased permeability of the capillaries, and stimulation of sensory nerve endings.
For example, if the release of histamine is slow enough to permit its inactivation before it enters the bloodstream, a local allergic reaction results. However, if histamine release is too fast for inactivation to be efficient, a full-blown anaphylactic reaction occurs.
H1 Antihistamines
The term antihistamine, refers to the classic H1-receptor blockers. These compounds do not influence the formation or release of histamine; rather, they block the receptor-mediated response of a target tissue. The H1 -receptor blockers can be divided into first- and second-generation drugs. The older first-generation drugs are still widely used because they are effective and inexpensive. However, most of these drugs penetrate the CNS and cause sedation. Furthermore, they tend to interact with other receptors, producing a variety of unwanted adverse effects. By contrast, the second-generation agents are specific for H1 receptors, and because they do not penetrate the blood-brain barrier, they show less CNS toxicity than the first-generation drugs. Among these agents desloratadine , fexofenadine , and loratadine show the least sedation.
A. Actions
The action of all the H1-receptor blockers is qualitatively similar. However, most of these blockers have additional effects unrelated to their blocking of H1 receptors; these effects probably reflect binding of the H1 antagonists to cholinergic, adrenergic, or serotonin receptors .
B. Therapeutic uses
1- Allergic and inflammatory conditions: H1-receptor blockers are useful in treating allergies caused by antigens acting on immunoglobulin E antibody-sensitized mast cells. For example, antihistamines are the drugs of choice in controlling the symptoms of allergic rhinitis and urticaria, because histamine is the principal mediator. However, the H1-receptor blockers are ineffective in treating bronchial asthma, because histamine is only one of several mediators of that condition. \[Note: Epinephrine has actions on smooth muscle that are opposite to those of histamine, and it acts at different receptors. Therefore, epinephrine is the drug of choice in treating systemic anaphylaxis and other conditions that involve massive release of histamine.] Glucocorticoids show greater anti-inflammatory effects than the H1 antihistamines.
2- Motion sickness and nausea: H1-receptor blockers, such as diphenhydramine , dimenhydrinate , cyclizine, meclizine, and hydroxyzine, are the most effective agents for prevention of the symptoms of motion sickness. The antihistamines prevent or diminish vomiting and nausea mediated by both the chemoreceptor and vestibular pathways. The antiemetic action of these medications seems to be due to their blockade of central H1 and muscarinic receptors.
3- Somnifacients: first-generation antihistamines, such as diphenhydramine and doxylamine , have strong sedative properties and are used in the treatment of insomnia. The use of first-generation H1 antihistamines is contraindicated in the treatment of individuals working in jobs where wakefulness is critical.
C. Pharmacokinetics
H1-receptor blockers are well absorbed after oral administration, with maximum serum levels occurring at 1 to 2 hours. The average plasma half-life is 4 to 6 hours except for meclizine, which has a half-life of 12 to 24 hours.H1-receptor blockers have high bioavailability and are distributed in all tissues, including the CNS. All first-generation H1 antihistamines and some second-generation H1 antihistamines, such as desloratadine and loratadine, are metabolized by the hepatic cytochrome P450 system. Cetirizine is excreted largely unchanged in the urine, and fexofenadine is excreted largely unchanged in the feces. After a single oral dose, the onset of action occurs within1 to 3 hours. The duration of action for many oral H1 antihistamines is at least 24 hours, facilitating once-daily dosing. They are most effective when used prophylactically before allergen exposure rather than as needed.
D. Adverse effects
First-generation H1-receptor blockers have a low specificity; that is, they interact not only with histamine receptors but also with muscarinic cholinergic receptors, I±-adrene rgic receptors, and serotonin receptors. Some side effects may be undesirable, and others may have therapeutic value.
Sedation: First-generation H1 antihistamines, such as chlorpheniramine , diphenhydramine, hydroxyzine , and promethazine , bind to H1 receptors and block the neurotransmitter effect of histamine in the CNS. The most frequently observed adverse reaction is sedation. Other central actions include tinnitus, fatigue, dizziness, lassitude , uncoordination, blurred vision, and tremors. Sedation is less common with the second-generation drugs, which do not readily enter the CNS. Second-generation H1 antihistamines are specific for H1 receptors and penetrate the CNS poorly. They show less sedation and other CNS effects.
Dry mouth: Oral antihistamines also exert weak anticholinergic effects, leading not only to a drying of the nasal passage but also to a tendency to dry the oral cavity. Blurred vision can occur as well with some drugs.
Drug interactions: Interaction of H1-receptor blockers with other drugs can cause serious consequences, such as potentiation of the effects of all other CNS depressants, including alcohol. Persons taking monoamine oxidase (MAO) inhibitors should not take antihistamines, because the MAO inhibitors can exacerbate the anticholinergic effects of the antihistamines. the first-generation antihistamines (diphenhydramine and others) have considerable anticholinergic (antimuscarinic) actions.
Overdoses: acute poisoning is relatively common, especially in young children. The most common and dangerous effects of acute poisoning are those on the CNS, including hallucinations, excitement, ataxia, and convulsions. If untreated, the patient may experience a deepening coma and
Histamine H2-Receptor Blockers
Histamine H2-receptor blockers have little, if any, affinity for H1 receptors. Although antagonists of the histamineH2 receptor (H2 antagonists) block the actions of histamine at all H2 receptors, their chief clinical use is as inhibitors of gastric acid secretion in the treatment of ulcers and heartburn. By competitively blocking the binding of histamine to H2 receptors, these agents reduce intracellular concentrations of c AMP and, thereby, secretion of gastric acid. The four drugs - cimetidine, ranitidine, famotidine, and nizatidine. potently inhibit (greater than 90 percent) basal, food-stimulated, and nocturnal secretion of gastric acid after a single dose. Cimetidine is the prototype histamine H2-receptor antagonist;however, its utility is limited by its adverse effect profile and drug interactions.
Actions: The histamine H2- receptor antagonists act selectively on H2 receptors in the stomach, blood vessels, and other sites. They are competitive antagonists of histamine and are fully reversible. These agents completely inhibit gastric acid secretion induced by histamine or gastrin. However, they only partially inhibit gastric acid secretion induced by acetylcholine or bethanechol.
Therapeutic uses:
Peptic ulcers: All four agents are equally effective in promoting healing of duodenal and gastric ulcers. Patients with NSAID-induced ulcers should be treated with PPIs, because these agents heal and prevent future ulcers better than H2 antagonists.
Acute stress ulcers: These drugs are useful in managing acute stress ulcers associated with major physical trauma in intensive care units. They are usually injected intravenously.
Gastroesophageal reflux disease: Low doses of H2 antagonists, appear to be effective for prevention and treatment of heartburn (gastroesophageal reflux), tolerance to the effects of H2 antagonists can be seen within 2 weeks of therapy.
Pharmacokinetics:
Cimetidine: Cimetidine and the other H2 antagonists are given orally, distribute widely throughout the body (including into breast milk and across the placenta), and are excreted mainly in the urine. Cimetidine normally has a short serum half-life. Approximately 30 percent of a dose of cimetidine is slowly inactivated by the liver and can interfere in the metabolism of many other drugs; the other 70 percent is excreted unchanged in the urine. The dosage of all these drugs must be decreased in patients with hepatic or renal failure. Cimetidine inhibits cytochrome P450 and can slow metabolism (and, thus, potentiate the action) of several drugs (for example, warfarin, diazepam,
phenytoin, quinidine, carbamazepine, theophylline , and imipramine, sometimes resulting in serious adverse clinical effects.
Ranitidine: Compared to cimetidine, ranitidine is longer acting and is five- to ten-fold more potent. Ranitidine has minimal side effects and does not produce the antiandrogenic or prolactin-stimulating effects of cimetidine . Unlike cimetidine , it does not inhibit the mixed-function oxygenase system in the liver and, thus, does not affect the concentrations of other drugs.
Famotidine: Famotidine is similar to ranitidine in its pharmacologic action, but it is 20 to 50 times more potent than cimetidine , and 3 to 20 times more potent than
Ranitidine .
Nizatidine: Nizatidine is similar to ranitidine in its pharmacologic action and potency. In contrast to cimetidine, ranitidine , and famotidine , which are metabolized by the liver, nizatidine is eliminated principally by the kidney. Because little first-pass metabolism occurs with nizatidine , its bioavailability is nearly 100 percent. No intravenous preparation is available.
Adverse effects: The most common side effects are headache, dizziness, diarrhea, and muscular pain. Other central nervous system effects (confusion, hallucinations) occur primarily in elderly patients or after intravenous administration. Cimetidine can also have endocrine effects, because it acts as antiandrogen. These effects include gynecomastia, galactorrhea and reduced sperm count.
Histamine is a chemical messenger that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in parts of the brain. Histamine has no clinical applications.
A. Location, synthesis, and release
1.Location: Histamine occurs in practically all tissues, , with high amounts found in lung, skin, and the gastrointestinal tract . It is found at high concentration in mast cells or basophiles.
2.Synthesis: Histamine is an amine formed by the decarboxylation of the amino acid histidine by histidine decarboxylase . In mast cells, histamine is stored in granules as an inactive complex composed of histamine and the, heparin. If histamine is not stored, it is rapidly inactivated by amine oxidase enzymes.
3- Release of histamine: The release of histamine may be the primary response to some stimuli. Stimuli causing the release of histamine from tissues include the destruction of cells as a result of cold, bacterial toxins, bee sting venoms, or trauma. Allergies and anaphylaxis can also trigger release of histamine.
B. Mechanism of action :Histamine released in response to various stimuli exerts its effects by binding to one or more of four types of histamine receptors - H1, H2, H3, and H4 receptors. H1 and H2 receptors are widely expressed and are the targets of clinically useful drugs. H3 and H4 receptors are expressed in only a few cell types, and their roles in drug action are unclear. All types of histamine receptors have seven transmembrane helical domains and transduce extracellular signals by way of G protein mediated second-messenger systems. Some of histamine's wide range of pharmacologic effects are mediated by both H1 and H2 receptors, whereas others are mediated by only one class. For example, the H1 receptors are important in producing smooth muscle contraction and increasing capillary permeability. Histamine promotes vasodilation by causing vascular endothelium to release nitric oxide. This chemical signal diffuses to the vascular smooth muscle, where it stimulates cyclic guanosine monophosphate production, causing vasodilation. Histamine H2 receptors mediate gastric acid secretion. In contrast, stimulation of H2 receptors enhances the production of cyclic adenosine monophosphate (cAMP) by adenylyl cyclase.
C. Role in allergy and anaphylaxis
The symptoms resulting from intravenous injection of histamine are similar to those associated with anaphylactic shock and allergic reactions. These include contraction of smooth muscle, stimulation of secretions, dilation and increased permeability of the capillaries, and stimulation of sensory nerve endings.
For example, if the release of histamine is slow enough to permit its inactivation before it enters the bloodstream, a local allergic reaction results. However, if histamine release is too fast for inactivation to be efficient, a full-blown anaphylactic reaction occurs.
H1 Antihistamines
The term antihistamine, refers to the classic H1-receptor blockers. These compounds do not influence the formation or release of histamine; rather, they block the receptor-mediated response of a target tissue. The H1 -receptor blockers can be divided into first- and second-generation drugs. The older first-generation drugs are still widely used because they are effective and inexpensive. However, most of these drugs penetrate the CNS and cause sedation. Furthermore, they tend to interact with other receptors, producing a variety of unwanted adverse effects. By contrast, the second-generation agents are specific for H1 receptors, and because they do not penetrate the blood-brain barrier, they show less CNS toxicity than the first-generation drugs. Among these agents desloratadine , fexofenadine , and loratadine show the least sedation.
A. Actions
The action of all the H1-receptor blockers is qualitatively similar. However, most of these blockers have additional effects unrelated to their blocking of H1 receptors; these effects probably reflect binding of the H1 antagonists to cholinergic, adrenergic, or serotonin receptors .
B. Therapeutic uses
1- Allergic and inflammatory conditions: H1-receptor blockers are useful in treating allergies caused by antigens acting on immunoglobulin E antibody-sensitized mast cells. For example, antihistamines are the drugs of choice in controlling the symptoms of allergic rhinitis and urticaria, because histamine is the principal mediator. However, the H1-receptor blockers are ineffective in treating bronchial asthma, because histamine is only one of several mediators of that condition. \[Note: Epinephrine has actions on smooth muscle that are opposite to those of histamine, and it acts at different receptors. Therefore, epinephrine is the drug of choice in treating systemic anaphylaxis and other conditions that involve massive release of histamine.] Glucocorticoids show greater anti-inflammatory effects than the H1 antihistamines.
2- Motion sickness and nausea: H1-receptor blockers, such as diphenhydramine , dimenhydrinate , cyclizine, meclizine, and hydroxyzine, are the most effective agents for prevention of the symptoms of motion sickness. The antihistamines prevent or diminish vomiting and nausea mediated by both the chemoreceptor and vestibular pathways. The antiemetic action of these medications seems to be due to their blockade of central H1 and muscarinic receptors.
3- Somnifacients: first-generation antihistamines, such as diphenhydramine and doxylamine , have strong sedative properties and are used in the treatment of insomnia. The use of first-generation H1 antihistamines is contraindicated in the treatment of individuals working in jobs where wakefulness is critical.
C. Pharmacokinetics
H1-receptor blockers are well absorbed after oral administration, with maximum serum levels occurring at 1 to 2 hours. The average plasma half-life is 4 to 6 hours except for meclizine, which has a half-life of 12 to 24 hours.H1-receptor blockers have high bioavailability and are distributed in all tissues, including the CNS. All first-generation H1 antihistamines and some second-generation H1 antihistamines, such as desloratadine and loratadine, are metabolized by the hepatic cytochrome P450 system. Cetirizine is excreted largely unchanged in the urine, and fexofenadine is excreted largely unchanged in the feces. After a single oral dose, the onset of action occurs within1 to 3 hours. The duration of action for many oral H1 antihistamines is at least 24 hours, facilitating once-daily dosing. They are most effective when used prophylactically before allergen exposure rather than as needed.
D. Adverse effects
First-generation H1-receptor blockers have a low specificity; that is, they interact not only with histamine receptors but also with muscarinic cholinergic receptors, I±-adrene rgic receptors, and serotonin receptors. Some side effects may be undesirable, and others may have therapeutic value.
Sedation: First-generation H1 antihistamines, such as chlorpheniramine , diphenhydramine, hydroxyzine , and promethazine , bind to H1 receptors and block the neurotransmitter effect of histamine in the CNS. The most frequently observed adverse reaction is sedation. Other central actions include tinnitus, fatigue, dizziness, lassitude , uncoordination, blurred vision, and tremors. Sedation is less common with the second-generation drugs, which do not readily enter the CNS. Second-generation H1 antihistamines are specific for H1 receptors and penetrate the CNS poorly. They show less sedation and other CNS effects.
Dry mouth: Oral antihistamines also exert weak anticholinergic effects, leading not only to a drying of the nasal passage but also to a tendency to dry the oral cavity. Blurred vision can occur as well with some drugs.
Drug interactions: Interaction of H1-receptor blockers with other drugs can cause serious consequences, such as potentiation of the effects of all other CNS depressants, including alcohol. Persons taking monoamine oxidase (MAO) inhibitors should not take antihistamines, because the MAO inhibitors can exacerbate the anticholinergic effects of the antihistamines. the first-generation antihistamines (diphenhydramine and others) have considerable anticholinergic (antimuscarinic) actions.
Overdoses: acute poisoning is relatively common, especially in young children. The most common and dangerous effects of acute poisoning are those on the CNS, including hallucinations, excitement, ataxia, and convulsions. If untreated, the patient may experience a deepening coma and
Histamine H2-Receptor Blockers
Histamine H2-receptor blockers have little, if any, affinity for H1 receptors. Although antagonists of the histamineH2 receptor (H2 antagonists) block the actions of histamine at all H2 receptors, their chief clinical use is as inhibitors of gastric acid secretion in the treatment of ulcers and heartburn. By competitively blocking the binding of histamine to H2 receptors, these agents reduce intracellular concentrations of c AMP and, thereby, secretion of gastric acid. The four drugs - cimetidine, ranitidine, famotidine, and nizatidine. potently inhibit (greater than 90 percent) basal, food-stimulated, and nocturnal secretion of gastric acid after a single dose. Cimetidine is the prototype histamine H2-receptor antagonist;however, its utility is limited by its adverse effect profile and drug interactions.
Actions: The histamine H2- receptor antagonists act selectively on H2 receptors in the stomach, blood vessels, and other sites. They are competitive antagonists of histamine and are fully reversible. These agents completely inhibit gastric acid secretion induced by histamine or gastrin. However, they only partially inhibit gastric acid secretion induced by acetylcholine or bethanechol.
Therapeutic uses:
Peptic ulcers: All four agents are equally effective in promoting healing of duodenal and gastric ulcers. Patients with NSAID-induced ulcers should be treated with PPIs, because these agents heal and prevent future ulcers better than H2 antagonists.
Acute stress ulcers: These drugs are useful in managing acute stress ulcers associated with major physical trauma in intensive care units. They are usually injected intravenously.
Gastroesophageal reflux disease: Low doses of H2 antagonists, appear to be effective for prevention and treatment of heartburn (gastroesophageal reflux), tolerance to the effects of H2 antagonists can be seen within 2 weeks of therapy.
Pharmacokinetics:
Cimetidine: Cimetidine and the other H2 antagonists are given orally, distribute widely throughout the body (including into breast milk and across the placenta), and are excreted mainly in the urine. Cimetidine normally has a short serum half-life. Approximately 30 percent of a dose of cimetidine is slowly inactivated by the liver and can interfere in the metabolism of many other drugs; the other 70 percent is excreted unchanged in the urine. The dosage of all these drugs must be decreased in patients with hepatic or renal failure. Cimetidine inhibits cytochrome P450 and can slow metabolism (and, thus, potentiate the action) of several drugs (for example, warfarin, diazepam,
phenytoin, quinidine, carbamazepine, theophylline , and imipramine, sometimes resulting in serious adverse clinical effects.
Ranitidine: Compared to cimetidine, ranitidine is longer acting and is five- to ten-fold more potent. Ranitidine has minimal side effects and does not produce the antiandrogenic or prolactin-stimulating effects of cimetidine . Unlike cimetidine , it does not inhibit the mixed-function oxygenase system in the liver and, thus, does not affect the concentrations of other drugs.
Famotidine: Famotidine is similar to ranitidine in its pharmacologic action, but it is 20 to 50 times more potent than cimetidine , and 3 to 20 times more potent than
Ranitidine .
Nizatidine: Nizatidine is similar to ranitidine in its pharmacologic action and potency. In contrast to cimetidine, ranitidine , and famotidine , which are metabolized by the liver, nizatidine is eliminated principally by the kidney. Because little first-pass metabolism occurs with nizatidine , its bioavailability is nearly 100 percent. No intravenous preparation is available.
Adverse effects: The most common side effects are headache, dizziness, diarrhea, and muscular pain. Other central nervous system effects (confusion, hallucinations) occur primarily in elderly patients or after intravenous administration. Cimetidine can also have endocrine effects, because it acts as antiandrogen. These effects include gynecomastia, galactorrhea and reduced sperm count.
0 التعليقات:
Post a Comment