Medical Pharmacology Topics
| Preliminary Outline |
Histamine Receptor Agonists 2-MethylhistamineBetazoleR-alpha-Methylhistamine Antihistamines  First Generation (H1)DiphenhydramineChlorpheniramineHydroxyzine Second Generation (H1)FexofenadineLoratadine
Cetirizine H2 BlockersCimetidineFamotidineNizatidine |
Mast cells are the predominant storage sites for histamine in most tissues, basophils in blood. These cells synthesize histamine and store it in secretory granules. Histamine is formed from histidine by decarboxylation, and is rapidly destroyed by histamine N-methyltransferase or by diamine oxidase. Systemically, histamine is an important mediator of inflammation in allergy and some non-allergic diseases.
Antigen contact produces a dermal wheal or angioedema (central raised area) and a surrounding flare or urticaria (red, flat halo). In allergic rhinitis, histamine stimulates mucus secretions, vascular permeability and edema. The conjunctiva also develops pruritus, swelling and redness similar to the dermal wheal and flares. Similar immune reactions mediate allergen effects at the bronchi Edema causes the wheal, while microvascular congestion causes the flare.
The allergic reaction is both immediate (< 20 min) and delayed (hours). Both early and late reactions involve histamine and other mediators, like the leukotrienes. In addition to antihistamines, other agents used to treat allergic reactions include leukotriene receptor antagonists (zileukon, zafirlukast), mast cell stabilizers (cromolyn), nasal costicosteroids and recombinant antibodies (not yet available clinically).
Scombroid fish poisoning is produced by scrombrotoxin, which is composed of histamine and other heat-stable, histamine-like substances like saurine. Poisoning symptoms resemble histamine eactions, and repiratory distress may devlop. Antihistamines provide symptomatic relief, but a bronchodilator should be administered to treat bronchospasm.
Histamine Receptors
Four histamine receptors have been identified: 2-methylhistamine is an H1 agonist, betazole is an H2 agonist and R-alpha-methylhistamine is an H3 agonist. The function of the H4 receptor is not known. Of the histamine agonists, only betazole is used clinically to induce gastric acid secretion. Histamine antagonists are more likely to be used clinically.
Histamine receptors are
most likely G-protein linked. H1 receptor activation proceeds
through the PLC-PI-IP3--DAG-PKC cascade. When H1 are activated
in the bronchi, IP3 releases Ca
from intracellular stores causing smooth muscle contraction. This leads to bronchoconstriction.
The H2
receptor stimulates adenylyl cyclase. cAMP mediates activation of the H/K
ATPase, i.e. secretion of H,
in gastric parietal cells, and tachycardia in myocites (may be tempered by the
baroreceptor reflex).
Activation of either H1 or H2 receptors increases vasodilation of vascular endothelium and elicits positive inotropic effects on myocytes through NO release. The NO-mediated vasodlation plays a part in the flare reaction.
In the CNS, histamine functions in sleep/wakefulness, hormone secretion and cardiovascular control. The H3 receptor modulates neurotransmission in the CNS and peripheral nerves dealing with airway, gastrointestinal and cardiovascular systems. H3 receptors inhibit (?) histamine release ad modulate acetylcholine, GABA, glutamate, norepinephrine and seratonin release in the CNS. Activation of H3 receptors in sensory C nerve fibers may ameliorate neurogenic inflammation and migrane.
Secreted histamine generates profound pharmacological effects locally and systemically, including anaphylaxis due to agents such as morphine or venoms. Histamine is released as a result of the interaction of antigens with IgE antibodies on mast cells. Its action on bronchial smooth muscle and blood vessels account in part for allergic symptoms (H1 and H2 receptors). It also has a major role in regulation of gastric secretions by inducing acid and peptin secretion (H2 receptors), formation of edema (wheal and flare) and stimulation of sensory nerve endings (H1 and H2).
Histamine acts on H1 and H2 receptors in the vasculature to increase vasodilation. H2 receptors in the heart increase inotropism (changes in contractility) and SA node rate. H1 receptors mediate bronchoconstriction in the lungs.
Antihistamines
H1 antagonists, usually referred to as anthistamines, are used to relieve allergic rhinitis, upper respiratory infections, dermatitis and other allergic conditions. There are two generations of antihistamines, the second generation has less sedative effects than te fist generation.
First generation antihistamines like diphenydramine, chlorpheniramine and hydroxyzine bind to histamine receptors competitively and nonselectively, and have some antimuscarinic properties. Since they acto on CNS receptors, 1st eneration agents produce sedation and psychometric impairment. Chlorpheniramine produces less sedation than diphenhydramine. Because they are competitive antagonists, they may not control sevee allergic reactions whenhistamine attains tissue concentrations up to 1000-fold more than the drug concentration.
Adverse effects of 1st generation antihistamines may be of four types in the CNS: stimulatory, neuropsychiatric, peripheral and depressive. Stimulatory effects includes seizures and muscle sasms, generally associated with overdosage or preeexisting epilepsy. Neuropsychiatric effects due to overdose includes hallucinations and psychosis or catatonic stupor. Anxiety may occur at normal doses. Peripheral adverse effects include paresthesias and anticholinergic effects. Coma may occur on overdose. Some antihistamines of either the 1sr or 2nd generations may cause weight gain.
Second generation antihistamines like fenofenadine, loratadine and cetrizine are competitive and selective for H1 receptors and are not sedative because they cannot cross the blood-brain barrier. At high cocentrations, they become non-competitive (?). Pretreatment with 2nd generation antihistamines decreases the antigen-induced release of inflamatory mediators in nasal tissue and secretions in allergic patients. Cetrizine pretreatment inhibits mediator release and basophil/eosinophil migration in th skin.
First pass metabolism by P450 may be extensive for loratidine and other 2nd generation agents. Loratidine is metaboized to descarboethoxyloratidine, which is the active agent. Inhibitors of CYP3A may decrease drug elimination and increase bioavailability (?) Although fexofenatine is not metabolized, eruthromycin increases is plasma concentration by inhibiting the enteroyte transporter P-glycoprotein. Lower doses of 2nd generation antihistamines may be needed in eldely patients or those with renal or hepatic impairment.
Indications
H1 antagonists decrease wheal size dose-dependently by decreasing vascular permeability and plasma protein leakage. They also limit the flare by decreasing vasodilation. In allergic rhinitis, H1 antagonists relieve some symptoms of conjuctivitis, but work better against nasal congestion if administered with b-adrenergic agonists like pseudoephedrine. Rhinorrhea associated with upper respiratory infections is responsive to the antimuscarinic properties of 1st generation antihistamines or an antimuscarinic like ipratropium bromide (as nasal spray). Second generation antihistamines may provide secodary relief of asthma. Both 1st and 2nd generation agents improve dermal pruitus and reduce the degree and duration of urticaria lesions, although an H2 antagonist may provide relief to refractory patients. Although epinephrine is the initial drug of choice to treat anaphilaxis. it may be combined with H1 antagonists to treat pruitus, angioedema and urticaria, and with H2 antagonists to diminish the effects of histamine in the myocardium and vasculature.
Diphehydramine is aso used for sedation and can reverse extrapyramidal effects of phenithiazides. Other 1st generation antihustamines have antiemetic activity and are used to treat vertigo or histamine-induced headaches.
Some responses to histamine, like wheal reaction and bronchoconstriction, are also in part due to other agents. Therefore, treatment with antihistamines may achieve a major but not complete recovery.
Gastric Acid Secretion
Gastric hydrogen ion secretion is controlled in three ways: neurocrine (acetylcholine), endocrine (gastrin) and paratacrine (histamine). H2 antagonists inhibit acid secretion induced by either betazole (H2 agonist), vagal stimuly, caffeine, pentagastrin or foog. They also reduce pepsin secretion. Overall, H2 antagonists like cimetidine, famotidine and nizatidine, increase gastric pH and promote ulcer healing. Inhibition of nocturnal acid secretion allows once daily dosing of H2 antagonists.
Cimetidine has an imidazol ring that tends to inhibit CYP450 and shows androgenic effects attributed to binding to the testosterone receptor. Patients in weak helth, i.e. renal failure, may experience confusion if the drug accumulates in the cerebrospinal fluid.
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